AAA-ATPase valosin-containing protein binds the transcription factor SREBP1 and promotes its proteolytic activation by rhomboid protease RHBDL4.
AAA-ATPase valosin-containing protein binds the transcription factor SREBP1 and promotes its proteolytic activation by rhomboid protease RHBDL4.
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DOI：
10.1016/j.jbc.2022.101936
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Ishibashi, Shun
中科院分区：
文献类型：
--
作者：
Shibuya, Koji;Ebihara, Ken;Ebihara, Chihiro;Sawayama, Nagisa;Isoda, Masayo;Yamamuro, Daisuke;Takahashi, Manabu;Nagashima, Shuichi;Ishibashi, Shun
含有Valosin的蛋白(VCP)是AAA-ATPase超家族成员之一，参与多种细胞功能。为了研究VCP在代谢紊乱中的病理生理学作用，我们产生了在VCP中携带A232E突变的敲入小鼠，VCP是一种已知的人类VCP致病变异。当杂合突变小鼠(A232E/+)喂饲高脂饲料时，我们观察到脂肪肝得到改善，转录因子类固醇调节元件结合蛋白1(SREBP1)的蛋白分解过程受到损害。野生型小鼠的进一步免疫共沉淀分析表明，VCP与SREBP1和RHBDL4在肝脏中存在相互作用，而在A232E/+小鼠中这些相互作用被减弱。与这些结果一致的是，我们表明在人肝细胞中VCP或RHBDL4的敲除或化学抑制会损害SREBP1的蛋白分解过程。最后，我们发现，糖蛋白78和HMG-CoA还原酶降解蛋白1等E3连接酶的敲除破坏了VCP与SREBP1的相互作用，并损害了SREBP1的蛋白降解过程。这些结果表明，VCP识别泛素化的SREBP1并将其招募到RHBDL4以促进其蛋白质降解过程。本研究揭示了SREBP1的一种新的蛋白降解加工途径，并可能导致开发新的治疗策略来治疗脂肪肝疾病。
Valosin-containing protein (VCP) is a member of AAA-ATPase superfamily involved in various cellular functions. To investigate the pathophysiological role of VCP in metabolic disorders, we generated knock-in mice bearing an A232E mutation in VCP, a known human VCP pathogenic variant. When heterozygous mutant mice (A232E/+) were fed a high-fat diet, we observed that fatty liver was ameliorated and the proteolytic processing of the transcription factor sterol regulatory element-binding protein 1 (SREBP1) was impaired. Further co-immunoprecipitation analysis in wildtype mice revealed interactions of VCP with SREBP1 and a rhomboid protease, RHBDL4, in the liver, and these interactions were attenuated in A232E/+ mice. Consistent with these results, we show that knockdown or chemical inhibition of VCP or RHBDL4 in human hepatocytes impaired the proteolytic processing of SREBP1. Finally, we found that knockdown of E3 ligases such as glycoprotein 78 and HMG-CoA reductase degradation protein 1 disrupted the interaction of VCP with SREBP1 and impaired the proteolytic processing of SREBP1. These results suggest that VCP recognizes ubiquitinylated SREBP1 and recruits it to RHBDL4 to promote its proteolytic processing. The present study reveals a novel proteolytic processing pathway of SREBP1 and may lead to development of new therapeutic strategies to treat fatty liver diseases.
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影响因子：
4
作者：
Nakano N;Ikeda HO;Hasegawa T;Muraoka Y;Iwai S;Tsuruyama T;Nakano M;Fuchigami T;Shudo T;Kakizuka A;Yoshimura N
通讯作者：
Yoshimura N
影响因子：
11.1
作者：
Nakano M;Imamura H;Sasaoka N;Yamamoto M;Uemura N;Shudo T;Fuchigami T;Takahashi R;Kakizuka A
通讯作者：
Kakizuka A
影响因子：
4.8
作者：
Lee, Jae-Jin;Park, Joon Kyu;Lee, Kong-Joo
通讯作者：
Lee, Kong-Joo
影响因子：
4.8
作者：
Noguchi, M;Takata, T;Kakizuka, A
通讯作者：
Kakizuka, A
影响因子：
29
作者：
Kuriyama, H;Liang, GS;Brown, MS
通讯作者：
Brown, MS