MFN2型
内质网
生物
细胞生物学
线粒体
泛素连接酶
GTP酶
泛素
生物化学
线粒体融合
线粒体DNA
基因
作者
Ayumu Sugiura,Shun Nagashima,Takeshi Tokuyama,Taku Amo,Yohei Matsuki,Satoshi Ishido,Yoshihisa Kudo,Heidi M. McBride,Toshifumi Fukuda,Nobuko Matsushita,Ryoko Inatome,Shigeru Yanagi
出处
期刊:Molecular Cell
[Elsevier]
日期:2013-07-01
卷期号:51 (1): 20-34
被引量:248
标识
DOI:10.1016/j.molcel.2013.04.023
摘要
Summary
The mitochondrial ubiquitin ligase MITOL regulates mitochondrial dynamics. We report here that MITOL regulates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) domain formation through mitofusin2 (Mfn2). MITOL interacts with and ubiquitinates mitochondrial Mfn2, but not ER-associated Mfn2. Mutation analysis identified a specific interaction between MITOL C-terminal domain and Mfn2 HR1 domain. MITOL mediated lysine-63-linked polyubiquitin chain addition to Mfn2, but not its proteasomal degradation. MITOL knockdown inhibited Mfn2 complex formation and caused Mfn2 mislocalization and MAM dysfunction. Sucrose-density gradient centrifugation and blue native PAGE retardation assay demonstrated that MITOL is required for GTP-dependent Mfn2 oligomerization. MITOL knockdown reduced Mfn2 GTP binding, resulting in reduced GTP hydrolysis. We identified K192 in the GTPase domain of Mfn2 as a major ubiquitination site for MITOL. A K192R mutation blocked oligomerization even in the presence of GTP. Taken together, these results suggested that MITOL regulates ER tethering to mitochondria by activating Mfn2 via K192 ubiquitination.
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