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10.1083/jcb.201308006
104,246,390
Mitochondrial fusion and structure depend on the dynamin-like GTPase OPA1, whose activity is regulated by proteolytic processing. Constitutive OPA1 cleavage by YME1L and OMA1 at two distinct sites leads to the accumulation of both long and short forms of OPA1 and maintains mitochondrial fusion. Stress-induced OPA1 proc...
10.1038/nrm3984
This paper describes mitoproteases that are involved in the processing of OPA1.
10.1073/pnas.1419581111
107,317,201
Significance Essential tremor is one of the most frequent movement disorders of humans, but its causes remain largely unknown. In a six-generation family with both essential tremor and Parkinson disease, we identified a rare missense mutation of HTRA2 as the causative allele. Family members homozygous for this allele w...
10.1038/nrm3984
References 124–126 describe some examples of mitoproteases that are associated with Parkinson disease.
10.1523/jneurosci.1532-09.2009
19,234,405
Paraplegin and AFG3L2 are ubiquitous nuclear-encoded mitochondrial proteins that form hetero-oligomeric paraplegin-AFG3L2 and homo-oligomeric AFG3L2 complexes in the inner mitochondrial membrane, named m -AAA proteases. These complexes ensure protein quality control in the inner membrane, jointly with a chaperone-like ...
10.1038/nrm3984
References 53 and 139–142 illustrate the key roles of mitoproteases in neuronal function.
10.1126/science.1065810
82,755,186
In Saccharomyces cerevisiae , more than 80% of the ∼6200 predicted genes are nonessential, implying that the genome is buffered from the phenotypic consequences of genetic perturbation. To evaluate function, we developed a method for systematic construction of double mutants, termed synthetic genetic array (SGA) analys...
10.1038/nrc2342
This study show how systematic genetic analysis can be performed to produce a global map of gene function.
10.1084/jem.20031562
61,040,990
Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE−CD25+ cells expressed L-selectin and C...
10.1038/nri2916
This study was the first to demonstrate that, based on their expression of homing receptors, T Reg cells could be subdivided into populations resembling naive T cells and effector- or memory-like T cells.
10.1126/science.1160062
62,608,017
Naturally occurring Foxp3 + CD4 + regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell–...
10.1038/nri2916
This study demonstrated that T Reg cells must express CTLA4 to prevent fatal lymphoproliferative autoimmune disease.
10.1126/science.1172702
125,148,104
Outfoxing Immune Excess Immune responses are kept in check by Foxp3-expressing CD4 + -regulatory T cells (T regs ) through a variety of mechanisms. Expression of specific transcription factors directs T reg responses into distinct T helper cell lineages; however, the transcription factors that regulate particular helpe...
10.1038/nri2916
Along with references 47 and 48, this study demonstrated that T Reg cells utilize distinct molecular programmes to control T H 1-, T H 2- and T H 17-type responses.
10.1084/jem.20041982
83,309,383
Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti–IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabe...
10.1038/nri2916
This paper showed that IL-2 produced by effector or memory CD4 + T cells controls T Reg cell homeostasis.
10.1126/science.1191996
103,533,100
Self-Renewing T Cells The homeostasis of cell populations within an organism can be achieved through a variety of mechanisms, including the differentiation of precursor populations, self-renewal of terminally differentiated cells, or by programming cells to be extremely long-lived. Regulatory T cells that express the t...
10.1038/nri2916
Along with reference 101, this study used lineage tracing to examine the phenotypical and functional stability of T Reg cells in different immune settings.
10.1084/jem.20090746
26,722,808
CD4+CD25+Foxp3+ natural regulatory T cells (T reg cells) maintain self-tolerance and suppress autoimmune diseases such as type 1 diabetes and inflammatory bowel disease (IBD). In addition to their effects on T cells, T reg cells are essential for maintaining normal numbers of dendritic cells (DCs): when T reg cells are...
10.1038/nri2916
This paper demonstrated that, in vivo , T Reg cell and DC homeostasis are intricately linked.
10.1126/science.7540771
27,991,519
The crystal structures of a cysteine-215→serine mutant of protein tyrosine phosphatase 1B complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor were determined. Peptide binding to the protein phosphatase was accompanied by a conformational c...
10.1038/nrc1837
The first example of PTP co-crystalized with substrate, providing insights into catalysis and determinants of substrate specificity.
10.1126/science.1067566
123,395,966
When bound by extracellular ligands, receptor tyrosine kinases (RTKs) on the cell surface transmit critical signals to the cell interior. Although signal termination is less well understood, protein tyrosine phosphatase–1B (PTP1B) is implicated in the dephosphorylation and inactivation of several RTKs. However, PTP1B r...
10.1038/nrc1837
Technically elegant study demonstrating that interactions between PTPs and their substrate occur in a spatially restricted manner.
10.1126/science.1096096
107,250,165
Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs ( PTPRF, PTPRG, PTPRT, PTPN3, PTPN1...
10.1038/nrc1837
A systematic and ambitious study demonstrating that inactivation of PTP is a frequent event in a common human tumour type.
10.4049/jimmunol.177.4.2080
62,075,258
Abstract Mesenchymal stem cells (MSCs) are not only able to evade the immune system, but they have also been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the pres...
10.1038/nri2395
This study showed that MSCs inhibit the maturation and antigen-presentation functions of DCs from cord blood and monocytes through soluble factors, resulting in a tolerogenic DC phenotype.
10.1182/blood-2005-07-2775
62,070,889
In recent years, mesenchymal stem cells (MSCs) have been shown to inhibit T-lymphocyte proliferation induced by alloantigens or mitogens. However, no substantial information is available regarding their effect on natural killer (NK) cells. Here we show that MSCs sharply inhibit IL-2-induced proliferation of resting NK ...
10.1038/nri2395
This paper showed the mutual interaction between MSCs and NK cells. MSC-mediated inhibition of NK-cell cytotoxicity is related to the down-regulation of surface expression of NK-cell activating receptors. Conversely, cytokine-activated NK cells can kill MSCs efficiently in vitro
10.1182/blood-2005-04-1496
20,353,979
Abstract We studied the immunoregulatory features of murine mesenchymal stem cells (MSCs) in vitro and in vivo. MSCs inhibited T-cell receptor (TCR)-dependent and -independent proliferation but did not induce apoptosis on T cells. Such inhibition was paired with a decreased interferon (IFN)-gamma and tumor necrosis fac...
10.1038/nri2395
This paper reported for the first time that intravenous injection of syngeneic MSCs in EAE-affected mice can be an effective treatment for autoimmune disease through the induction of peripheral T-cell tolerance.
10.1182/blood-2004-09-3696
83,116,599
Abstract It has been shown that mesenchymal stem cells (MSCs) induce T cells to become unresponsive. We characterized the phenotype of these T cells by dissecting the effect of MSCs on T-cell activation, proliferation, and effector function. For this purpose, an in vitro murine model was used in which T-cell responses ...
10.1038/nri2395
This study showed that MSC-mediated inhibition of cyclin D2 expression by stimulated T cells leads to cell-division arrest, an important mechanism that maintains the inhibition of T-cell proliferation.
10.1634/stemcells.2005-0008
38,232,230
Abstract Mesenchymal stem cells (MSCs) inhibit the proliferation of HLA-unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4+ and CD8+ T lymphocytes, as well as of natural killer (NK) c...
10.1038/nri2395
This paper gives important insights into the cross-talk between MSCs and immune cells, showing that MSC-mediated inhibition of T-cell and NK-cell functions is increased by IFN γ secreted by target cells, leading to the production of IDO by MSCs.
10.1182/blood-2005-07-2657
20,529,373
Abstract Human mesenchymal stem cells (hMSCs) suppress T-cell and dendritic-cell function and represent a promising strategy for cell therapy of autoimmune diseases. Nevertheless, no information is currently available on the effects of hMSCs on B cells, which may have a large impact on the clinical use of these cells. ...
10.1038/nri2395
In this paper, MSCs were shown to inhibit in vitro B-cell proliferation, differentiation to plasma cells and subsequent antibody secretion through paracrine mechanisms.
10.1073/pnas.0508945102
41,532,478
Stem/progenitor cells from bone marrow and other sources have been shown to repair injured tissues by differentiating into tissue-specific phenotypes, by secreting chemokines, and, in part, by cell fusion. Here we prepared the stem/progenitor cells from human bone marrow (MSCs) and implanted athem into the dentate gyru...
10.1038/nri2395
MSCs implanted in the hippocampus of mice induced proliferation of endogenous neural stem cells expressing SOX2 and their migration and differentiation into both neural precursors and mature neural cells.
10.1152/ajprenal.00007.2005
124,941,766
Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamp...
10.1038/nri2395
In this paper, it is shown that MSCs rapidly home to the kidney following acute renal failure, where they release anti-inflammatory cytokines and protect renal cells from apoptosis without persistent engraftment or transdifferentiation.
10.1126/science.271.5251.990
122,986,995
Variants of λ repressor and cytochrome b 562 translated from messenger RNAs without stop codons were modified by carboxyl terminal addition of an ssrA -encoded peptide tag and subsequently degraded by carboxyl terminal-specific proteases present in both the cytoplasm and periplasm of Escherichia coli . The tag appears ...
10.1038/nrg3963
This work reveals the function of tmRNA that rescues ribosomes from truncated mRNA lacking stop codons through the process of trans -translation.
10.1126/science.1069588
62,605,134
Pyrrolysine is a lysine derivative encoded by the UAG codon in methylamine methyltransferase genes of Methanosarcina barkeri . Near a methyltransferase gene cluster is the pylT gene, which encodes an unusual transfer RNA (tRNA) with a CUA anticodon. The adjacent pylS gene encodes a class II aminoacyl-tRNA synthetase th...
10.1038/nrg3963
This work describes the discovery of twenty-second proteinogenic amino acid.
10.1101/gr.119974.110
123,192,552
While translational stop codon readthrough is often used by viral genomes, it has been observed for only a handful of eukaryotic genes. We previously used comparative genomics evidence to recognize protein-coding regions in 12 species of Drosophila and showed that for 149 genes, the open reading frame following the sto...
10.1038/nrg3963
This work reveals signatures of protein-coding evolution in the sequences downstream of stop codons in many genes in Drosophila species. This is strong evidence that stop codon readthrough has important functional roles in these organisms.
10.1073/pnas.1218613110
20,373,397
Despite the fact that the genetic code is known to vary between organisms in rare cases, it is believed that in the lifetime of a single cell the code is stable. We found Acetohalobium arabaticum cells grown on pyruvate genetically encode 20 amino acids, but in the presence of trimethylamine (TMA), A. arabaticum dynami...
10.1038/nrg3963
This paper describes a microorganism that uses alternative genetic codes depending on its environment.
10.1073/pnas.1322190111
105,393,763
Significance During translation, ribosomes decode mRNAs in a sequential fashion. In this paper, we report the discovery of more than 80 translational bypassing elements (byps) 27–55 nt long in mitochondrial protein-coding regions of the yeast Magnusiomyces capitatus. We demonstrate experimentally that byps are retained...
10.1038/nrg3963
From 1988 until the publication of this paper in 2014, only a single naturally occurring case of translational bypassing was known. In this work the authors describe numerous cases of such bypassing that occur during the translation of mRNA in the mitochondria of the yeast Magnusiomyces capitatus
10.1126/science.1250691
80,730,926
The canonical genetic code is assumed to be deeply conserved across all domains of life with very few exceptions. By scanning 5.6 trillion base pairs of metagenomic data for stop codon reassignment events, we detected recoding in a substantial fraction of the >1700 environmental samples examined. We observed extensi...
10.1038/nrg3963
In this work the authors used metagenome sequences to analyse the occurrence of stop codon reassignment in organisms from different environments. Among several intriguing findings was a bacteriophage that modifies the genetic code of its host during infection.
10.7554/elife.01179
103,502,250
Ribosomes can read through stop codons in a regulated manner, elongating rather than terminating the nascent peptide. Stop codon readthrough is essential to diverse viruses, and phylogenetically predicted to occur in a few hundred genes in Drosophila melanogaster, but the importance of regulated readthrough in eukaryot...
10.1038/nrg3963
In this work the authors used ribosome profiling to analyse the protein-coding potential of the Drosophila melanogaster genome and confirmed the widespread occurrence of stop codon readthrough in this organism.
10.1126/science.1164748
81,083,563
Strict one-to-one correspondence between codons and amino acids is thought to be an essential feature of the genetic code. However, we report that one codon can code for two different amino acids with the choice of the inserted amino acid determined by a specific 3′ untranslated region structure and location of the dua...
10.1038/nrg3963
This work describes a unique case of codon redefinition that involves a sense codon.
10.1099/0022-1317-82-5-1013
19,705,334
The 2A region of the aphthovirus foot-and-mouth disease virus (FMDV) polyprotein is only 18 aa long. A ‘primary’ intramolecular polyprotein processing event mediated by 2A occurs at its own C terminus. FMDV 2A activity was studied in artificial polyproteins in which sequences encoding reporter proteins flanked the 2A s...
10.1038/nrg3963
In this work the authors demonstrated that ribosomes can interrupt continuous elongation of polypeptide chains without interruption of mRNA decoding, thus producing two peptide products from a single ORF.
10.1126/scitranslmed.3003761
125,013,839
Adoptively transferred chimeric antigen receptor T cells have stable stem cell–like persistence for at least a decade and more than 500 years of patient safety.
10.1038/nrc.2016.97
From the first-in-human clinical trials of CAR T cells, decade-long persistence, stable engraftment and safety in more than 500 years of patient follow-up were demonstrated.
10.1158/0008-5472.can-15-0159
62,401,418
Abstract Target-mediated toxicity is a major limitation in the development of chimeric antigen T-cell receptors (CAR) for adoptive cell therapy of solid tumors. In this study, we developed a strategy to adjust the affinities of the scFv component of CAR to discriminate tumors overexpressing the target from normal tissu...
10.1038/nrc.2016.97
References 66 and 67 show that the affinity of CAR binding domains can be tuned to discriminate tumours overexpressing the target from normal tissues that express it at physiological levels.
10.1126/scitranslmed.3005661
80,046,196
A therapeutic monoclonal antibody specific for the intracellular oncoprotein Wilms tumor 1 treats human leukemias in mice.
10.1038/nrc.2016.97
Description of the targeting of an intracellular tumour antigen with monoclonal antibody, laying the groundwork for CAR targeting of intracellular antigens when presented in an HLA complex.
10.1158/0008-5472.can-14-3321
18,249,859
Abstract Adoptive immunotherapy using autologous T cells endowed with chimeric antigen receptors (CAR) has emerged as a powerful means of treating cancer. However, a limitation of this approach is that autologous CAR T cells must be generated on a custom-made basis. Here we show that electroporation of transcription ac...
10.1038/nrc.2016.97
Description of a strategy to generate universal allogeneic T cells through gene editing by TALENs.
10.1182/blood-2013-03-478255
102,110,215
Key Points Allogeneic-donor–derived cells can be genetically modified to eliminate expression of HLA-A. HLA-A disruption from donor cells is a step toward generating allogeneic cells as an off-the-shelf therapeutic.
10.1038/nrc.2016.97
Description of a strategy to generate universal T cells through gene editing by ZFNs.
10.1126/science.aab4077
104,251,129
Keeping a leash on cancer-killing cells Redirecting the immune system to attack tumor cells is proving to be an effective therapy against cancer. However, when patients are exposed to T cells engineered to recognize and attack cancer cells, there is a risk of runaway or excessive activity or of off-target effects, both...
10.1038/nrc.2016.97
A novel intracellular 'on switch' is described for gene-modified T cells, which may greatly enhance control of CAR T cell effector function. See also ref. 126
10.1126/scitranslmed.3006597
38,245,080
Human T cells that are reversibly inhibited upon contact with antigen protect bystander tissues from immune destruction.
10.1038/nrc.2016.97
A description of inhibitory CARs enabling engineered T cell inhibition to avoid on-target, off-tumour CAR T cell reactivity.
10.1091/mbc.e06-01-0080
103,577,880
The endoplasmic reticulum (ER) contains both cisternal and reticular elements in one contiguous structure. We identified rtn1Δ in a systematic screen for yeast mutants with altered ER morphology. The ER in rtn1Δ cells is predominantly cisternal rather than reticular, yet the net surface area of ER is not significantly ...
10.1038/nrm2179
References 7 and 8 are key studies that identify the reticulon family of proteins as factors that shape the ER in yeast and animal cells.
10.1083/jcb.200304030
28,274,198
Myo4p is a nonessential type V myosin required for the bud tip localization of ASH1 and IST2 mRNA. These mRNAs associate with Myo4p via the She2p and She3p proteins. She3p is an adaptor protein that links Myo4p to its cargo. She2p binds to ASH1 and IST2 mRNA, while She3p binds to both She2p and Myo4p. Here we show that...
10.1038/nrm2179
Identification of myosin as the motor driving the active inheritance of cortical ER in yeast. See reference 83 for related evidence for the role of myosin in Golgi inheritance.
10.1091/mbc.e03-04-0229
38,933,112
Sec3p is a component of the exocyst complex that tethers secretory vesicles to the plasma membrane at exocytic sites in preparation for fusion. Unlike all other exocyst structural genes, SEC3 is not essential for growth. Cells lacking Sec3p grow and secrete surprisingly well at 25°C; however, late markers of secretion,...
10.1038/nrm2179
References 35 and 36 are important papers demonstrating that the exocyst is a spatial landmark for secretion and ER inheritance.
10.1073/pnas.0602595103
58,362,745
The new Golgi in the protozoan parasite Trypanosoma brucei grows near to the old and adjacent to the growing new endoplasmic reticulum exit site. Growth is now shown to be at least a two-stage process, in which a representative matrix marker (GRASP) and enzyme (GntB) are delivered to the site of assembly, followed ≈10 ...
10.1038/nrm2179
Hints at underlying mechanistic similarities between centrosome duplication and Golgi biogenesis in these organisms.
10.1126/science.1119969
122,728,211
Centrins are highly conserved components of the centrosome, which in the parasitic protozoan T. brucei comprises the basal body and nucleates the flagellum used for locomotion. Here, we found TbCentrin2 in an additional bi-lobed structure near to the Golgi apparatus. One lobe was associated with the old Golgi, and the ...
10.1038/nrm2179
Identification of centrin-2 as a template for Golgi biogenesis in trypanosomes.
10.1091/mbc.e05-02-0155
62,598,941
Golgi inheritance during mammalian cell division occurs through the disassembly, partitioning, and reassembly of Golgi membranes. The mechanisms responsible for these processes are poorly understood. To address these mechanisms, we have examined the identity and dynamics of Golgi proteins within mitotic membranes using...
10.1038/nrm2179
References 91 and 92 provide evidence for the recycling of Golgi proteins to the ER in mitosis.
10.1073/pnas.161283998
100,816,352
The pericentriolar stacks of Golgi cisternae undergo extensive reorganization during mitosis in mammalian cells. GM130 and GRASP65 (Golgi reassembly stacking protein of 65 kDa) are Golgi-associated proteins that are targets of mitotic kinases, and they have also been implicated in the reorganization of the Golgi struct...
10.1038/nrm2179
References 108–109 identified a link between GRASP proteins and cell-cycle regulation in both yeast and mammalian cells. This might take the form of a checkpoint reading out the status of the Golgi. Also refer to references 105, 110 and 111.
10.1002/ajmg.a.36711
18,952,295
22q11.2 deletion syndrome is one of the most common microdeletion syndromes. Most patients have a deletion resulting from a recombination of low copy repeat blocks LCR22‐A and LCR22‐D. Loss of the TBX1 gene is considered the most important cause of the phenotype. A limited number of patients with smaller, overlapping d...
10.1038/nrdp.2015.71
164A Importantly, this paper reports cases of nested deletions of LCR22B–LCR22D, LCR22C–LCR22D and beyond, demonstrating that genes within the LCR22B–LCR22D regions result in features typically associated with the full LCR22A–LCR22D deletion.
10.1242/dev.028902
80,029,636
Elucidating the gene regulatory networks that govern pharyngeal arch artery(PAA) development is an important goal, as such knowledge can help to identify new genes involved in cardiovascular disease. The transcription factor Tbx1 plays a vital role in PAA development and is a major contributor to cardiovascular disease...
10.1038/nrdp.2015.71
In mice, the gastrulation brain homeobox 2 ( Gbx2 ) gene was found to be crucial in the pharyngeal ectoderm to signal to adjacent neural crest cells, which was required to form the aortic arch and branching vessels.
10.1073/pnas.1401923111
99,747,593
Significance The 22q11.2 deletion is the most common known genetic cause of congenital heart disease (CHD). The haploinsufficiency of TBX1 has been identified as the cause of CHD. Using mouse models of the disease, we found that reduced dosage of p53 suppresses the Tbx1 mutant phenotype. Tbx1 and p53 proteins coregulat...
10.1038/nrdp.2015.71
Genetic rescue is the gold standard for future therapeutics for 22q11.2DS. This is the first paper demonstrating that genetic rescue can take place by reducing the levels of p53.
10.1002/ajmg.c.31435
82,944,004
Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000–4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life‐threatening...
10.1038/nrdp.2015.71
This paper provides a current state of the art perspective on developmental trajectories with appropriate interventions.
10.1182/blood-2003-08-2824
81,767,242
Abstract Patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) typically exhibit thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. The immunodeficiency that results from the thymic hypoplasia has been extensively described and consists primarily of T-cell...
10.1038/nrdp.2015.71
The consequences of thymic hypoplasia were elucidated in this paper. It highlights the dynamic nature of immunodeficiency over time in this syndrome.
10.1192/bjp.bp.111.097139
18,110,571
Background People with 22q11.2 deletion syndrome (velo-cardio-facial syndrome) have a 30-fold risk of developing schizophrenia. In the general population the schizophrenia phenotype includes a cognitive deficit and a decline in academic performance preceding the first episode of psychosis in a subgroup of patients. Fin...
10.1038/nrdp.2015.71
This paper presents a longitudinal data study on cognitive development in a large cohort of children.
10.1192/bjp.bp.114.151837
17,905,883
Background Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples. Aims To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clo...
10.1038/nrdp.2015.71
This paper is notable as it is the first report on the functional outcome of a large group (>100 subjects) of adults with 22q11.2 DS.
10.1126/science.1373520
107,323,159
Interleukin-1β (IL-1β) mediates a wide range of immune and inflammatory responses. The active cytokine is generated by proteolytic cleavage of an inactive precursor. A complementary DNA encoding a protease that carries out this cleavage has been cloned. Recombinant expression in COS-7 cells enabled the cells to process...
10.1038/nrm1496
References 15 and 16 report the identification of the first caspase.
10.1073/pnas.221580098
41,512,072
Caspases form a family of proteinases required for the initiation and execution phases of apoptosis. Distinct proapoptotic stimuli lead to activation of the initiator caspases-8 and -9, which in turn activate the common executioner caspases-3 and -7 by proteolytic cleavage. Whereas crystal structures of several active ...
10.1038/nrm1496
References 56 and 57 describe the activation mechanism for an effector caspase, caspase-7.
10.1101/gad.953002
109,156,999
The Jun kinase (JNK) pathway has been characterized for its role in stimulating AP-1 activity and for modulating the balance between cell growth and death during development, inflammation, and cancer. Six families of mammalian kinases acting at the level of JNKKK have emerged as upstream regulators of JNK activity (MLK...
10.1038/nrm906
This paper provides evidence that Slipper is the Drosophila MLK that is downstream of the GTPase dRac and controls the JNK pathway during epithelial migration in the developing fly embryo.
10.1128/mcb.22.12.4073-4085.2002
102,250,654
ABSTRACT Tiam1 and Ras-GRF1 are guanine nucleotide exchange factors (GEFs) that activate the Rac GTPase. The two GEFs have similar N-terminal regions containing pleckstrin homology domains followed by coiled-coils and additional sequences that function together to allow regulated GEF activity. Here we show that this N-...
10.1038/nrm906
This work shows that MLK3 can activate the p38 signalling pathway in a Tiam1/JIP2-dependent fashion.
10.1128/mcb.19.10.7245
125,149,429
ABSTRACT Activation of the c-Jun NH 2 -terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is mediated by a protein kinase cascade. This signaling mechanism may be coordinated by the interaction of components of the protein kinase cascade with scaffold proteins. The JNK-interacting protein (JIP) grou...
10.1038/nrm906
This paper describes the association of MLKs with the JIP scaffold proteins for the regulation of the JNK pathway.
10.1002/jmr.2266
103,712,116
The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the strength of binding. We discuss, in detail, methodological developments that occurred in the docking field in 2010 and 2011, with a particular focus on the more difficult...
10.1038/nrc3690
This is a comprehensive review on the latest docking software, docking methods and scoring techniques used for in silico screening.
10.1002/cmdc.201200107
61,989,724
Abstract Protein interactions are increasingly appreciated as targets in small‐molecule drug discovery. The interaction between the adapter protein S100A10 and its binding partner annexin A2 is a potentially important drug target. To obtain small‐molecule starting points for inhibitors of this interaction, a three‐dime...
10.1038/nrc3690
This is a prime example of the protein-based pharmacophore VS approach.
10.1126/science.274.5292.1531
125,118,575
A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands. The approach is called “SAR by NMR” because structure-activity relationships (SAR) are obtained from ...
10.1038/nrc3690
This seminal paper introduced the concept of using fragments for drug discovery and the potential of low-affinity hit compounds as the basis for drug development.
10.1126/science.7529940
125,081,343
The x-ray crystal structure of the complex between human growth hormone (hGH) and the extracellular domain of its first bound receptor (hGHbp) shows that about 30 side chains from each protein make contact. Individual replacement of contact residues in the hGHbp with alanine showed that a central hydrophobic region, do...
10.1038/nrc3690
This is the paper that introduced the concept of the hot spot in protein–protein interfaces.
10.4049/jimmunol.0801165
122,768,334
Abstract The formation of lymph nodes is a complex process crucially controlled through triggering of LTβR on mesenchymal cells by LTα1β2 expressing lymphoid tissue inducer (LTi) cells. This leads to the induction of chemokines to attract more hematopoietic cells and adhesion molecules to retain them. In this study, we...
10.1038/nri2832
Here the authors propose that tight clustering of LTi cells is needed to allow TRANCER triggering on LTi cells, which is needed for the generation of the first LTα 1 β 2 -expressing LTi cells.
10.1084/jem.20061959
19,282,428
The Id2 transcriptional repressor is essential for development of natural killer (NK) cells, lymphoid tissue–inducing (LTi) cells, and secondary lymphoid tissues. Id2 was proposed to regulate NK and LTi lineage specification from multipotent progenitors through suppression of E proteins. We report that NK cell progenit...
10.1038/nri2832
By combining ID2 deficiency, which is required for the generation of LTi cells, with deficiency of E2A-encoded proteins, which are required for differentiation towards the B cell lineage, this article shows that ID2 is needed to suppress the activity of E proteins, as Id2 −/− E2a −/− mice have LTi cells and form lymph ...
10.1084/jem.20091436
109,107,226
The eye is protected by the ocular immunosurveillance system. We show that tear duct–associated lymphoid tissue (TALT) is located in the mouse lacrimal sac and shares immunological characteristics with mucosa-associated lymphoid tissues (MALTs), including the presence of M cells and immunocompetent cells for antigen up...
10.1038/nri2832
In this study, the authors show that the development of lymphoid structures associated with the tear ducts occurs independently of LTi cells.
10.1073/pnas.0700591104
79,393,224
CXC chemokine ligand 13 (CXCL13), CC chemokine ligand 21 (CCL21), and CCL19 are constitutively expressed in secondary lymphoid organs, where they control the placement of lymphocytes and dendritic cells. However, these chemokines are also inducibly expressed in the lung after influenza infection. Here we show that, in ...
10.1038/nri2832
By depletion of all secondary lymphoid organs, the authors show the crucial role of the homeostatic chemokines CXCL13, CCL21 and CCL19 for local B and T cell responses in the lungs.
10.1126/science.1159407
41,545,054
The prevention of autoimmunity requires the elimination of self-reactive T cells during their development and maturation. The expression of diverse self-antigens by stromal cells in the thymus is essential to this process and depends, in part, on the activity of the autoimmune regulator ( Aire ) gene. Here we report th...
10.1038/nri2832
This paper shows that AIRE-expressing stromal cells in secondary lymphoid organs are involved in deleting autoreactive T cells through expression of self antigens.
10.1002/art.33368
19,830,187
Abstract Objective Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients. ...
10.1038/nri3261
References 20, 21 and 22 describe recessive mutations in the PSMB8 immunoproteasome subunit that cause autoinflammatory syndromes.
10.1126/science.1156995
104,344,602
The inhalation of airborne pollutants, such as asbestos or silica, is linked to inflammation of the lung, fibrosis, and lung cancer. How the presence of pathogenic dust is recognized and how chronic inflammatory diseases are triggered are poorly understood. Here, we show that asbestos and silica are sensed by the Nalp3...
10.1038/nri3261
References 34–36 demonstrate activation of the NLRP3 inflammasome through environmental particulate stimuli and the adjuvant aluminium hydroxide (alum).
10.1084/jem.20102049
79,800,337
Reactive oxygen species (ROS) have an established role in inflammation and host defense, as they kill intracellular bacteria and have been shown to activate the NLRP3 inflammasome. Here, we find that ROS generated by mitochondrial respiration are important for normal lipopolysaccharide (LPS)-driven production of severa...
10.1038/nri3261
This study demonstrates a mitochondrial source for the ROS that are observed in TRAPS and suggests that enhanced pro-inflammatory cytokine production results from ROS-triggered MAPK signalling.
10.4049/jimmunol.1100613
83,381,355
Abstract A common denominator among the multiple damage-inducing agents that ultimately lead to activation of NLRP3 has not yet been identified. Recently, production of reactive oxygen species (ROS) has been suggested to act as a common event upstream of the NLRP3 inflammasome machinery. Because de novo translation of ...
10.1038/nri3261
Reference 47 was the first study to suggest that dysfunctional mitochondria may activate the NLRP3 inflammasome, although references 45 and 50 suggest that ROS also have a role in this process through increasing the transcription of inflammasome component proteins.
10.1073/pnas.0914118107
103,994,020
TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammati...
10.1038/nri3261
A study describing cooperativity between functional wild-type TNFR1 and TRAPS-associated mutant TNFR1 that leads to enhanced inflammatory responses through MAPK activation.
10.1002/art.22491
101,681,549
Abstract Objective The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1 , encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structu...
10.1038/nri3261
References 99 and 100 describe the inflammatory syndromes linked to dominant mutations in the NLRP3 gene.
10.1126/science.1220030
82,179,224
Keeping Baby Safe Because half the genes from a developing fetus are inherited from the father, from the mother's perspective, a fetus is “foreign.” How, then, does the maternal immune system tolerate the fetus? Nancy et al. (p. 1317 ) found that careful regulation of cellular recruitment signals allowed for fetal tole...
10.1038/nri.2017.64
This study demonstrates the role of the decidua in the recruitment of immune cells and the regulation of this process by epigenetic factors.
10.1002/jnr.22368
82,669,067
Abstract Adverse neurological outcome is a major cause of long‐term morbidity in ex‐preterm children. To investigate the effect of parturition and inflammation on the fetal brain, we utilized two in vivo mouse models of preterm birth. To mimic the most common human scenario of preterm birth, we used a mouse model of in...
10.1038/nri.2017.64
This study suggests that inflammation-induced preterm birth, and not the process of preterm birth itself, may result in neuroinflammation and alter fetal neuronal morphology.
10.4049/jimmunol.1300661
20,017,352
Abstract Preterm birth is the major cause of neonatal mortality and morbidity, and bacterial infections that ascend from the lower female reproductive tract are the most common route of uterine infection leading to preterm birth. The uterus and growing fetus are protected from ascending infection by the cervix, which c...
10.1038/nri.2017.64
This study demonstrates that a viral infection of the cervix has consequences for protection against ascending bacteria during pregnancy.
10.1126/science.aad2571
125,322,951
Mom's bugs shape of spring immunity In utero, babies are relatively microbe-free but are quickly colonized at birth. These early microbial residents help to shape our immune systems. Gomez de Agüero et al. wondered whether the maternal microbiome also affects the of springs' immune system during gestation. To do this, ...
10.1038/nri.2017.64
This study investigates the role of the maternal microbiota, and shows that pups born to mothers transiently colonized in pregnancy are better able to avoid inflammatory responses to microbial molecules and the penetration of intestinal microbes than are pups born to mothers that had not been transiently colonized.
10.4049/jimmunol.1000289
60,526,297
Abstract Pandemics pose a more significant threat to pregnant women than to the nonpregnant population and may have a detrimental effect on the well being of the fetus. We have developed an animal model to evaluate the consequences of a viral infection characterized by lack of fetal transmission. The experiments descri...
10.1038/nri.2017.64
This study demonstrates that viral infection of the placenta may sensitize the pregnant mother to bacterial products and promote preterm labour.
10.4049/jimmunol.1601824
20,067,248
Abstract Pregnant women have greater mortality and complications associated with viral infections compared with the general population, but the reason for the increased susceptibility is not well defined. Placenta type I IFN is an important immune modulator and protects the pregnancy. We hypothesized that loss of place...
10.1038/nri.2017.64
The findings of this study highlight the role of fetal–placental type I IFNs in the modulation of viral infection in the mother and fetus.
10.1126/science.aaf6116
104,271,249
Zika virus tested in human brain organoids The pernicious and resilient Aedes mosquito is rapidly spreading Zika virus (ZIKV) through the Americas. ZIKV infection mostly causes mild disease, but in some patients, nervous system involvement is indicated. A particular worry is an observed correlation between infection of...
10.1038/nri.2017.64
The results of this study suggest that Zika virus abrogates neurogenesis during human brain development.
10.1126/science.1106885
17,641,375
γδ T cell receptors (TCRs), αβ TCRs, and antibodies are the three lineages of somatically recombined antigen receptors. The structural basis for ligand recognition is well defined for αβ TCR and antibodies but is lacking for γδ TCRs. We present the 3.4 Å structure of the murine γδ TCR G8 bound to its major histocompat...
10.1038/nri2781
This paper details the first crystal structure of a γδ TCR in complex with its cognate ligand, revealing an unusual mode of molecular interaction compared with the docking of αβ TCRs on classical MHC molecules.
10.1126/science.1063916
20,881,220
The localization of γδ T cells within epithelia suggests that these cells may contribute to the down-regulation of epithelial malignancies. We report that mice lacking γδ cells are highly susceptible to multiple regimens of cutaneous carcinogenesis. After exposure to carcinogens, skin cells expressed Rae-1 and H60, maj...
10.1038/nri2781
This paper shows the first strong evidence for a crucial role of γδ T cells in tumour immunosurveillance.
10.4049/jimmunol.0900013
59,262,629
Abstract Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. We previously reported that C57BL/6 mice repeatedly exposed to the ubiquitous microorganism Bacill...
10.1038/nri2781
This study, as well as references 24 and 36, showed that γδ T cells are prominent sources of IL-17 during infection.
10.1073/pnas.0903895106
83,454,947
Some γδ and αβ T lymphocytes exhibit an “innate” phenotype associated with rapid cytokine responses. The PLZF transcription factor is essential for the innate phenotype of NKT cells. This report shows that PLZF is likewise responsible for the innate, NKT-like phenotype of Vγ1+Vδ6.3/Vδ6.4+ cells. TCR cross-linking induc...
10.1038/nri2781
This study provides strong evidence for molecular and developmental similarities between mouse invariant NKT cells and an NKT cell-like subset of γδ T cells with hepatosplenic tropism.
10.4049/jimmunol.173.6.3660
124,867,170
Abstract γδ T cells have a direct role in resolving the host immune response to infection by eliminating populations of activated macrophages. Macrophage reactivity resides within the Vγ1/Vδ6.3 subset of γδ T cells, which have the ability to kill activated macrophages following infection with Listeria monocytogenes (Lm...
10.1038/nri2781
This study, and reference 65, provides strong evidence for a key role of IL-17-producing γδ T cells in several immunopathological processes.
10.1126/science.7916481
16,676,264
Indirect evidence implicates γδ T cells in the cross-regulation of CD4 αβ T cell responses. Adoptive transfer of small numbers of γδ T cells from ovalbumin (OVA)-tolerant mice selectively suppressed T H 2 -dependent immunoglobulin E(IgE) antibody production without affecting parallel IgG responses. Challenge of these γ...
10.1038/nri2781
This report was an early demonstration that mouse γδ T cells can regulate IgE responses.
10.4049/jimmunol.165.8.4174
99,447,354
Abstract Coxsackievirus B3 infections of C57BL/6 mice, which express the MHC class II IA but not IE Ag, results in virus replication in the heart but minimal myocarditis. In contrast, Bl.Tg.Eα mice, which are C57BL/6 mice transgenically induced to express IE Ag, develop significant myocarditis upon Coxsackievirus B3 in...
10.1038/nri2781
The paper shows early evidence that functional roles of γδ T cell subsets correlate with their expressed TCRs.
10.1084/jem.20151613
103,698,824
Inflammasomes activate caspase-1 in response to cytosolic contamination or perturbation. This inflammatory caspase triggers the opening of the GSDMD pore in the plasma membrane, resulting in lytic cell death called pyroptosis. We had previously assumed that pyroptosis releases intracellular bacteria to the extracellula...
10.1038/nri.2016.147
This paper shows that PITs are a mechanism to hold intracellular bacteria in place after lytic cell death.
10.1073/pnas.1412767111
81,647,284
Significance Receptor-interacting kinase-3 (RIP3) and its substrate mixed lineage kinase domain-like protein (MLKL) are now recognized as the core cellular regulators of programmed necrosis. Programmed necrosis is thought be involved in host defense against pathogens, but the mechanistic studies on the topic are still ...
10.1038/nri.2016.147
This study shows that Ripk3 −/− mice are susceptible to HSV-1 infection.
10.1038/ncomms8515
39,243,210
Abstract TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activ...
10.1038/nri.2016.147
This study describes the effect of Casp8 −/− mutation upon TLR3 signalling and NLRP3 priming.
10.1126/science.233.4761.359
123,315,449
While the spring phytoplankton bloom in Newfoundland coastal waters is in progress during April and May, at water temperatures between -1° and +2°C, bacterial growth and respiratory rates remain low. Microbial community respiration is not measurable at -0.2°C. Particulate materials that would be utilized by microorgani...
10.1038/nrmicro2115
Pomeroy and Deibel provide the original statement of the Pomeroy hypothesis, outlining temperature effects on bacterial growth rates and the consequences of low bacterial growth for marine food webs.
10.1073/pnas.0811302106
38,240,255
Carbon uptake by marine phytoplankton, and its export as organic matter to the ocean interior (i.e., the “biological pump”), lowers the partial pressure of carbon dioxide ( p CO 2 ) in the upper ocean and facilitates the diffusive drawdown of atmospheric CO 2 . Conversely, precipitation of calcium carbonate by marine p...
10.1038/nrmicro2115
Together with Reference 57, this study explains how climate change will affect mixing in the oceans.
10.1158/1055-9965.epi-07-2843
79,391,267
Abstract The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most abundant carcinogens in smokeless tobacco products. NNK uptake by measurement of the urinary metabolites 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL) has been reported in ...
10.1038/nrc824
Supports the hypothesis that β-adrenergic-receptor pathways are involved in NNK-induced lung carcinogenesis. The authors conclude that retention of NNAL in lungs of smokers and smokeless-tobacco users is best explained by the presence of β-adrenergic receptors.
10.1091/mbc.12.7.1973
37,696,809
The protein kinase C (PKC) is a family of serine/threonine kinases that are key regulatory enzymes involved in growth, differentiation, cytoskeletal reorganization, tumor promotion, and migration. We investigated the functional involvement of PKC isotypes and of E-cadherin in the regulation of the locomotion of six hum...
10.1038/nrc824
Evidence that noradrenaline binds to β-adrenergic receptors to induce the migration of colon cancer cells. These findings provide strong support for our theory that, in addition to adenocarcinomas in the lungs and pancreas, adenocarcinomas in the colon might benefit from therapy and prevention with β-blockers or inhibi...
10.1126/science.290.5499.2114
80,989,129
Large segmental duplications cover much of the Arabidopsis thaliana genome. Little is known about their origins. We show that they are primarily due to at least four different large-scale duplication events that occurred 100 to 200 million years ago, a formative period in the diversification of the angiosperms. A bette...
10.1038/nrg1064
This article defines the extent and timing of duplication events on the basis of genomic sequence, and illustrates important principles about the genomic duplications that have been found in all flowering plants examined so far.
10.1101/gad.997902
38,804,403
Cell differentiation is essential for the development of multicellular organisms. In flowering plants, the haploid male gametophytes (pollen grains) are generated in the anther from reproductive cells called microsporocytes. Several types of somatic cells ensure successful pollen development, and thus reproduction. How...
10.1038/nrg1064
This study addresses the important question of how pre-meiotic cells are specified in the anther, and indicates that there is a trade off between somatic and pre-germinal cell proliferation that is regulated through the kinase defined in the genetic study.
10.1093/genetics/153.2.933
103,673,103
Abstract In angiosperm ovules and anthers, the hypodermal cell layer provides the progenitors of meiocytes. We have previously reported that the multiple archesporial cells1 (mac1) mutation identifies a gene that plays an important role in the switch of the hypodermal cells from the vegetative pathway to the meiotic (s...
10.1038/nrg1064
A genetic and anatomical study of the consequences of the excess proliferation of germinal cells at the expense of strictly somatic cells in maize, for comparison with Zhao et al . (reference 30) who examined a parallel phenomenon in Arabidopsis
10.1093/genetics/100.3.475
83,334,734
ABSTRACT Among 38 reciprocal translocations between the maize B chromosome and the proximal region of the long arm of chromosome 10 were six interchanges associated with reduced endosperm development. These six have breakpoints that are the most proximal of the set and constitute a graded series with those broken neare...
10.1038/nrg1064
This report shows that the crucial parental genome ratios that are required for normal seed development occur in the endosperm, by separately manipulating ratios in the embryo and endosperm using B-A translocations.
10.1126/science.280.5362.446
20,693,759
The gametophytic maternal effect mutant medea ( mea ) shows aberrant growth regulation during embryogenesis in Arabidopsis thaliana . Embryos derived from mea eggs grow excessively and die during seed desiccation. Embryo lethality is independent of the paternal contribution and gene dosage. The mea phenotype is consist...
10.1038/nrg1064
First report of an imprinted gene in Arabidopsis , which, along with reference 70, begins to define the scope of parent-of-origin effects.
10.1126/science.287.5459.1820
103,112,048
The first artery and vein of the vertebrate embryo assemble in the trunk by migration and coalescence of angioblasts to form endothelial tubes. The gridlock ( grl ) mutation in zebrafish selectively perturbs assembly of the artery (the aorta). Here it is shown that grl encodes a basic helix-loop-helix (bHLH) protein be...
10.1038/nrg1158
This paper reports how bHLH proteins determine arterial cell fate.
10.1073/pnas.182296499
62,613,027
Vascular endothelial growth factor (VEGF) is an angiogenic protein with neurotrophic and neuroprotective effects. Because VEGF promotes the proliferation of vascular endothelial cells, we examined the possibility that it also stimulates the proliferation of neuronal precursors in murine cerebral cortical cultures and i...
10.1038/nrg1158
This study documents how the prototype angiogenic factor VEGF affects neurogenesis.
10.1126/science.1072165
107,340,586
Axons are guided along specific pathways by attractive and repulsive cues in the extracellular environment. Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules, including netrins, Slits, semaphorins, and ephrins. Guidance cues steer axons by regulating cytos...
10.1038/nrg1158
A recent overview of the cellular and molecular mechanisms of axon guidance.