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J Biol Chem ; 295(7): 2084-2096, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31822558


The Maf proteins, including c-Maf, MafA, and MafB, are critical transcription factors in myelomagenesis. Previous studies demonstrated that Maf proteins are processed by the ubiquitin-proteasome pathway, but the mechanisms remain elusive. This study applied MS to identify MafB ubiquitination-associated proteins and found that the ubiquitin-specific protease USP7 was present in the MafB interactome. Moreover, USP7 also interacted with c-Maf and MafA and blocked their polyubiquitination and degradation. Consistently, knockdown of USP7 resulted in Maf protein degradation along with increased polyubiquitination levels. The action of USP7 thus promoted Maf transcriptional activity as evidenced by luciferase assays and by the up-regulation of the expression of Maf-modulated genes. Furthermore, USP7 was up-regulated in myeloma cells, and it was negatively associated with the survival of myeloma patients. USP7 promoted myeloma cell survival, and when it was inhibited by its specific inhibitor P5091, myeloma cell lines underwent apoptosis. These results therefore demonstrated that USP7 is a deubiquitinase of Maf proteins and promotes MM cell survival in association with Maf stability. Given the significance of USP7 and Maf proteins in myeloma genesis, targeting the USP7/Maf axle is a potential strategy to the precision therapy of MM.

Life Sci ; 226: 91-97, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978348


The liver is importantly metabolic and detoxifying organ in the body. When various pathogenic factors affect the liver, the normal physiological and biochemical functions are weakened, resulting in liver diseases. Liver fibrosis is a common pathological process of chronic liver disease. During hepatic fibrosis the changes in the components of the extracellular matrix (ECM) provide an environment that facilitates tissue remodeling. Among these ECM components, periostin, a glycoprotein that is predominantly secreted by osteoblasts and their precursors, playing an important role in bone formation, has attracted great attention. Periostin not only involves in bone metabolism, but also functions in modulating the cell fate determination, proliferation, inflammatory responses, even tumorigenesis of many other tissues and organs including liver. In different categories of liver disease patients, the serum and liver tissue levels of periostin were closely related to the decline of liver function, and the pathological stage. Numerous animal studies and experiments in vitro subsequently demonstrated that the abnormal expression of periostin resulted in metabolic disorders, liver inflammation, fibrosis and even tumorigenesis. Here we review the current progress on the role of periostin in pathologic pathways of liver system to explore whether periostin is a potential therapeutic target for the treatment of different liver diseases.

Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/fisiologia , Hepatopatias/metabolismo , Animais , Diferenciação Celular , Doença Crônica , Matriz Extracelular , Células Estreladas do Fígado , Hepatite , Humanos , Fígado/metabolismo , Fígado/fisiologia , Cirrose Hepática , Hepatopatias/fisiopatologia , Transdução de Sinais
Redox Biol ; 19: 375-387, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30237126


It is generally recognized that hepatic fibrogenesis is an end result of increased extracellular matrix (ECM) production from the activation and proliferation of hepatic stellate cells (HSCs). An in-depth understanding of the mechanisms of HSC necroptosis might provide a new therapeutic strategy for prevention and treatment of hepatic fibrosis. In this study, we attempted to investigate the effect of curcumol on necroptosis in HSCs, and further to explore the molecular mechanisms. We found that curcumol ameliorated the carbon tetrachloride (CCl4)-induced mice liver fibrosis and suppressed HSC proliferation and activation, which was associated with regulating HSC necroptosis through increasing the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3). Moreover, curcumol promoted the migration of RIPK1 and RIPK3 into necrosome in HSCs. RIPK3 depletion impaired the anti-fibrotic effect of curcumol. Importantly, we showed that curcumol-induced RIPK3 up-regulation significantly increased mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization. ROS scavenger, N-acetyl-L-cysteine (NAC) impaired RIPK3-mediated necroptosis. In addition, our study also identified that the activation of c-Jun N-terminal kinase1/2 (JNK1/2) was regulated by RIPK3, which mediated curcumol-induced ROS production. Down-regulation of RIPK3 expression, using siRIPK3, markedly abrogated JNK1/2 expression. The use of specific JNK1/2 inhibitor (SP600125) resulted in the suppression of curcumol-induced ROS production and mitochondrial depolarization, which in turn, contributed to the inhibition of curcumol-triggered necroptosis. In summary, our study results reveal the molecular mechanism of curcumol-induced HSC necroptosis, and suggest a potential clinical use of curcumol-targeted RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling for the treatment of hepatic fibrosis.

Células Estreladas do Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Necrose/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sesquiterpenos/farmacologia , Acetilcisteína/farmacologia , Animais , Tetracloreto de Carbono/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
Biomed Pharmacother ; 97: 339-348, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29091883


Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules. The recent finding that LDs can be selectively degraded by the lysosomal pathway of autophagy through a process termed lipophagy has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in various diseases including liver disease. Lipophagy was originally described in hepatocytes, where it is critical for maintaining cellular energy homeostasis in obesity and metabolic syndrome. In vitro and in vivo studies have demonstrated the selective uptake of LDs by autophagosomes, and inhibition of autophagy has been shown to reduce the ß-oxidation of free fatty acids due to the increased accumulation of lipids and LDs. The identification of lipophagy as a new process dedicated to cellular lipid removal has mapped autophagy as an emerging player in cellular lipid metabolism. Pharmacological or genetic modulation of lipophagy might point to possible therapeutic strategies for combating a broad range of liver diseases. This review summarizes recent work focusing on lipophagy and liver disease as well as highlighting challenges and future directions of research. On the other hand, it also offers a glimpse into different strategies that have been used in experimental models to counteract excessive pathological lipophagy in the prevention and treatment of liver disease.

Autofagia/fisiologia , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Hepatopatias/metabolismo , Animais , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Humanos , Lipólise/fisiologia , Hepatopatias/terapia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/terapia , Obesidade/metabolismo , Obesidade/terapia