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HRES-1/Rab4 促进自噬过程中 LC3(+)自噬体的形成和线粒体的积累。

HRES-1/Rab4 promotes the formation of LC3(+) autophagosomes and the accumulation of mitochondria during autophagy.

机构信息

Departments of Medicine, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.

Departments of Medicine, State University of New York, Upstate Medical University, Syracuse, New York, United States of America ; Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.

出版信息

PLoS One. 2014 Jan 3;9(1):e84392. doi: 10.1371/journal.pone.0084392. eCollection 2014.

DOI:10.1371/journal.pone.0084392
PMID:24404161
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3880286/
Abstract

HRES-1/Rab4 is a small GTPase that regulates endocytic recycling. It has been colocalized to mitochondria and the mechanistic target of rapamycin (mTOR), a suppressor of autophagy. Since the autophagosomal membrane component microtubule-associated protein light chain 3 (LC3) is derived from mitochondria, we investigated the impact of HRES-1/Rab4 on the formation of LC3(+) autophagosomes, their colocalization with HRES-1/Rab4 and mitochondria, and the retention of mitochondria during autophagy induced by starvation and rapamycin. HRES-1/Rab4 exhibited minimal baseline colocalization with LC3, which was enhanced 22-fold upon starvation or 6-fold upon rapamycin treatment. Colocalization of HRES-1/Rab4 with mitochondria was increased >2-fold by starvation or rapamycin. HRES-1/Rab4 overexpression promoted the colocalization of mitochondria with LC3 upon starvation or rapamycin treatment. A dominant-negative mutant, HRES-1/Rab4(S27N) had reduced colocalization with LC3 and mitochondria upon starvation but not rapamycin treatment. A constitutively active mutant, HRES-1/Rab4(Q72L) showed diminished colocalization with LC3 but promoted the partitioning of mitochondria with LC3 upon starvation or rapamycin treatment. Phosphorylation-resistant mutant HRES-1/Rab4(S204Q) showed diminished colocalization with LC3 but increased partitioning to mitochondria. A newly discovered C-terminally truncated native isoform, HRES-1/Rab4(1-121), showed enhanced localization to LC3 and mitochondria without starvation or rapamycin treatment. HRES-1/Rab4(1-121) increased the formation of LC3(+) autophagosomes in resting cells, while other isoforms promoted autophagosome formation upon starvation. HRES-1/Rab4, HRES-1/Rab4(1-121), HRES-1/Rab4(Q72L) and HRES-1/Rab4(S204Q) promoted the accumulation of mitochondria during starvation. The specificity of HRES-1/Rab4-mediated mitochondrial accumulation is indicated by its abrogation by dominant-negative HRES-1/Rab4(S27N) mutation. The formation of interconnected mitochondrial tubular networks was markedly enhanced by HRES-1/Rab4(Q72L) upon starvation, which may contribute to the retention of mitochondria during autophagy. The present study thus indicates that HRES-1/Rab4 regulates autophagy through promoting the formation of LC3(+) autophagosomes and the preservation of mitochondria.

摘要

HRES-1/Rab4 是一种小 GTPase，可调节内体再循环。它与线粒体和雷帕霉素靶蛋白（mTOR）共定位，后者是自噬的抑制剂。由于自噬体膜成分微管相关蛋白轻链 3（LC3）来自线粒体，因此我们研究了 HRES-1/Rab4 对 LC3(+)自噬体形成、与 HRES-1/Rab4 和线粒体的共定位以及自噬诱导过程中维持线粒体的影响饥饿和雷帕霉素。HRES-1/Rab4 与 LC3 的基础共定位最小，饥饿或雷帕霉素处理后增强 22 倍。饥饿或雷帕霉素处理后，HRES-1/Rab4 与线粒体的共定位增加了 >2 倍。HRES-1/Rab4 的过表达促进了饥饿或雷帕霉素处理时线粒体与 LC3 的共定位。显性负突变体 HRES-1/Rab4(S27N)在饥饿时与 LC3 和线粒体的共定位减少，但雷帕霉素处理时则不然。组成型激活突变体 HRES-1/Rab4(Q72L)与 LC3 的共定位减少，但在饥饿或雷帕霉素处理时促进了线粒体与 LC3 的分区。磷酸化抗性突变体 HRES-1/Rab4(S204Q)与 LC3 的共定位减少，但增加了与线粒体的分区。一种新发现的 C 端截短的天然同工型 HRES-1/Rab4(1-121)，无需饥饿或雷帕霉素处理即可增强与 LC3 和线粒体的定位。HRES-1/Rab4(1-121)增加了静息细胞中 LC3(+)自噬体的形成，而其他同工型则在饥饿时促进自噬体的形成。HRES-1/Rab4、HRES-1/Rab4(1-121)、HRES-1/Rab4(Q72L)和 HRES-1/Rab4(S204Q)在饥饿时促进了线粒体的积累。显性负突变体 HRES-1/Rab4(S27N)的阻断表明 HRES-1/Rab4 介导的线粒体积累具有特异性。HRES-1/Rab4 调节线粒体积累的特异性通过其介导的形成互联的线粒体管状网络得到显著增强，这可能有助于自噬过程中保留线粒体。因此，本研究表明 HRES-1/Rab4 通过促进 LC3(+)自噬体的形成和维持线粒体来调节自噬。

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