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Nature ; 577(7788): 109-114, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827280


Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.

Nat Commun ; 8(1): 814, 2017 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-28993672


Ubiquitin ligase TRAF6, together with ubiquitin-conjugating enzyme Ubc13/Uev1, catalyzes processive assembly of unanchored K63-linked polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways. However, what domain and how it functions to enable TRAF6's processivity are largely uncharacterized. Here, we find TRAF6 coiled-coil (CC) domain is crucial to enable its processivity. The CC domain mediates TRAF6 oligomerization to ensure efficient long polyubiquitin chain assembly. Mutating or deleting the CC domain impairs TRAF6 oligomerization and processive polyubiquitin chain assembly. Fusion of the CC domain to the E3 ubiquitin ligase CHIP/STUB1 renders the latter capable of NF-κB activation. Moreover, the CC domain, after oligomerization, interacts with Ubc13/Ub~Ubc13, which further contributes to TRAF6 processivity. Point mutations within the CC domain that weaken TRAF6 interaction with Ubc13/Ub~Ubc13 diminish TRAF6 processivity. Our results reveal that the CC oligomerization primes its interaction with Ubc13/Ub~Ubc13 to confer processivity to TRAF6 ubiquitin ligase activity.Ubiquitin ligase TRAF6 catalyzes assembly of free polyubiquitin chains for TAK1 activation in the IL-1R/TLR pathways, but the mechanism underlying its processivity is unclear. Here, the authors show that TRAF6 coiled-coil oligomerization domain primes its interaction with Ubc13/Ub~Ubc13 to confer processivity.

Fator 6 Associado a Receptor de TNF/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Células HEK293 , Humanos , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Poliubiquitina/metabolismo , Domínios Proteicos , Fator 6 Associado a Receptor de TNF/química , Fator 6 Associado a Receptor de TNF/genética , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
J Comp Physiol B ; 187(7): 931-943, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28353178


Oxygen is a vital element in aquatic environments. The concentration of oxygen to which aquatic organisms are exposed is influenced by salinity, water temperature, weather, and surface water runoff. Hypoxia has a serious effect on fish populations, and can lead to the loss of habitat and die-offs. Therefore, in the present study we used next-generation sequencing technology to characterize the transcriptomes of Pelteobagrus vachelli and identified 70 candidate genes in the HIF-1 signaling pathway that are important for the hypoxic response in all metazoan species. For the first time, the present study reported the effects of acute hypoxia and reoxygenation on oxygen sensors, respiratory metabolism, and hematology indices in P. vachelli. The predicted physiological adjustments show that P. vachelli's blood oxygen-carrying capacity was increased through increased RBC, HB, and SI after hypoxia exposure. Glycolysis-related enzyme activities (PFK, HK, and PK) and LDH in the brain and liver also increased, indicating a rise in anaerobic metabolism. The observed reduction in oxidative enzyme level (CS) in the liver during hypoxia suggests a concomitant depression in aerobic metabolism. There were significant increases in oxygen sensor mRNA expression and HIF-1α protein expression during hypoxia and reoxygenation exposure, suggesting that the HIF-1 signaling pathway was activated in the liver and brain of P. vachelli in response to acute hypoxia and reoxygenation. Our findings suggest that oxygen sensors (e.g., HIF-1α) of P. vachelli are potentially useful biomarkers of environmental hypoxic exposure. These data contribute to a better understanding of the molecular mechanisms of the hypoxia signaling pathway in fish under hypoxia and reoxygenation.

Peixes-Gato/metabolismo , Metabolismo Energético , Proteínas de Peixes/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Oxigênio/metabolismo , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Adaptação Fisiológica , Animais , Encéfalo/metabolismo , Peixes-Gato/sangue , Peixes-Gato/genética , Proteínas de Peixes/genética , Regulação Enzimológica da Expressão Gênica , Hipóxia/sangue , Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Fígado/metabolismo , Oxigênio/sangue , RNA Mensageiro/genética , Fatores de Tempo
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(5): 3551-2, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26260177


The complete mitochondrial genome of Pseudobagrus vachelli has been sequenced. The mitochondrial genome is 16 529 bp in length, with the base composition of 31.61% A, 26.88% T, 26.55% C, and 14.96% G, containing 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes and a major non-coding control region (D-loop region). The gene order and orientation are similar with some typical fish species. The data will provide useful molecular information for phylogenetic studies concerning P. vachelli and its related species.

Peixes-Gato/genética , Genoma Mitocondrial , Mitocôndrias/genética , Análise de Sequência de DNA/métodos , Animais , Composição de Bases , Ordem dos Genes , Genes de RNAr , Tamanho do Genoma , Filogenia , RNA de Transferência/genética
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(4): 2414-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26016879


In this study, the mitochondrial genome of Oxyeleotris lineolatus was first determined. The length of entire mtDNA sequence was 16,522 bp with (A + T) content of 53.81%, and it contained 13 protein-coding genes, two rRNAs, 22 tRNAs, and a control region. The gene order and the orientation are similar to some typical fish species. The data will provide useful molecular information for phylogenetic studies concerning O. lineolatus and its related species.

Genoma Mitocondrial , Perciformes/classificação , Perciformes/genética , Filogenia , Sequenciamento Completo do Genoma , Animais , Composição de Bases , Evolução Molecular , Genes Mitocondriais , Tamanho do Genoma , Fases de Leitura Aberta , Análise de Sequência de DNA
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(6): 4191-4192, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-25648919


In the present of study, we have reported the complete mitochondrial DNA sequence of the hybrid of Pelteobagrus fulvidraco (♀) × Pelteobagrus vachelli (♂) that is obtained by artificial hybridization. The total length of the mitochondrial genome is 16,527 bp, with the base compositions of 30.84% A, 25.54% T, 28.22% C, and 15.40% G. It contains two ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and a major non-coding control region (D-loop region). The arrangement of these genes is same as that observed in the teleosts. All protein initiation codons are ATG, except for COX1 that begins with GTG. The complete mitogenome of the hybrid of P. fulvidraco (♀) × P. vachelli (♂) provides an important data set for the exploration of mitochondrial inheritance mechanism. The termination-associated sequence and critical central conserved sequences (CSB-D, CSB-E and CSB-F) are also detected.

Peixes-Gato/genética , Quimera/genética , Proteínas de Peixes/genética , Genoma Mitocondrial , Proteínas Mitocondriais/genética , RNA Ribossômico/genética , RNA de Transferência/genética , RNA/genética , Animais , RNA Mitocondrial