F-box/WD Repeat-Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal-Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice
F-box/WD Repeat-Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal-Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice
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F-box/WD 含有重复序列的蛋白 5 介导细胞凋亡信号调节激酶 1 的泛素化并加剧小鼠非酒精性脂肪性肝炎。
DOI：
10.1002/hep.30537
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发表时间：
2019-12-01
期刊：
影响因子：
13.5
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Bai, Lan;Chen, Ming-Ming;Li, Hongliang
抑制细胞凋亡信号调节激酶1（ASK 1）的活化已成为治疗非酒精性脂肪性肝炎（NASH）的一个有前途的靶点。多种形式的翻译后修饰决定了ASK 1的活性。除了磷酸化，最近的研究表明，泛素化是ASK 1激活所必需的。然而，调节ASK 1泛素化和激活的内源性因子仍然不清楚。在这项研究中，我们确定了E3连接酶Skp 1-Cul 1-F-box（SCF）蛋白F-box/WD重复包含蛋白5（FBXW 5）作为一个关键的内源性激活剂的ASK 1泛素化。FBXW 5是SCF复合物（SCFFbxw 5）的核心成分，在NASH发展过程中直接与肝细胞中的ASK 1相互作用并使其泛素化。一项体内研究表明，FBXW 5的肝细胞特异性过表达加剧了饮食诱导的全身和肝脏代谢紊乱，以及肝脏中ASK 1相关的丝裂原活化蛋白激酶（MAPK）信号转导的激活。相反，FBXW 5的肝细胞特异性缺失显著阻止了这些异常的进展。在机械上，FBXW 5促进了Lys 63连接的泛素添加到ASK 1，从而加剧了ASK 1-c-Jun N-末端激酶/p38 MAPK信号传导、炎症和脂质积累。此外，我们证明了FBXW 5的N-末端（S1）和C-末端（S3）分别竞争性地消除FBXW 5对ASK 1激活的功能，并作为NASH进展的有效抑制剂。结论：SCF（Fbxw 5）是NASH中ASK 1泛素化的重要激活因子。FBXW 5（S1）或FBXW 5（S3）模拟药物的开发和特异性消除ASK 1泛素化依赖性激活的小分子抑制剂的筛选是NASH治疗的可行方法。
Inhibition of apoptosis signal-regulating kinase 1 (ASK1) activation has emerged as a promising target for the treatment of nonalcoholic steatohepatitis (NASH). Multiple forms of posttranslational modifications determine the activity of ASK1. In addition to phosphorylation, recent studies revealed that ubiquitination is essential for ASK1 activation. However, the endogenous factor that regulates ASK1 ubiquitination and activation remains poorly defined. In this study, we identified the E3 ligase Skp1-Cul1-F-box (SCF) protein F-box/WD repeat-containing protein 5 (FBXW5) as a key endogenous activator of ASK1 ubiquitination. FBXW5 is the central component of the SCF complex (SCFFbxw5) that directly interacts with and ubiquitinates ASK1 in hepatocytes during NASH development. An in vivo study showed that hepatocyte-specific overexpression of FBXW5 exacerbated diet-induced systemic and hepatic metabolic disorders, as well as the activation of ASK1-related mitogen-activated protein kinase (MAPK) signaling in the liver. Conversely, hepatocyte-specific deletion of FBXW5 significantly prevented the progression of these abnormalities. Mechanically, FBXW5 facilitated the addition of Lys63-linked ubiquitin to ASK1 and thus exacerbated ASK1-c-Jun N-terminal kinase/p38 MAPK signaling, inflammation, and lipid accumulation. Furthermore, we demonstrated that the N-terminus (S1) and C-terminus (S3) of FBXW5 respectively and competitively ablate the function of FBXW5 on ASK1 activation and served as effective inhibitors of NASH progression. Conclusion: This evidence strongly suggests that SCF(Fbxw5 )is an important activator of ASK1 ubiquitination in the context of NASH. The development of FBXW5(S1) or FBXW5(S3)-mimicking drugs and screening of small-molecular inhibitors specifically abrogating ASK1 ubiquitination-dependent activation are viable approaches for NASH treatment.