Endosomal Rab cycles regulate Parkin-mediated mitophagy

• 檜作, 洋平

  Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science・Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda

• Wang, Chunxin

  Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda

• Sarraf, Shireen A

  Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda

• Münch, Chiristian

  Department of Cell Biology, Harvard Medical School, Boston・Institute of Biochemistry II, School of Medicine, Goethe University

• Kikuchi, Reika

  Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, Tokyo

• Noda, Nobuo N

  Institute of Microbial Chemistry, Tokyo

• Hizukuri, Yohei

  Institute for Frontier Life and Medical Sciences, Kyoto University

• Kanemaki, Masato T

  Division of Molecular Cell Engineering, National Institute of Genetics, Research Organization of Information and Systems, Mishima・Department of Genetics, SOKENDAI・Division of Molecular Cell Engineering, National Institute of Genetics, ROIS

• Harper, Wade

  Department of Cell Biology, Harvard Medical School, Boston

• Tanaka, Keiji

  Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science

• Matsuda, Noriyuki

  Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science

• Youle, Richard J

  Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda

抄録

Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.

収録刊行物

• eLife

  eLife 7 e31326-, 2018-01-23

  eLife Sciences Organisation, Ltd.

キーワード

• RESEARCH ARTICLE
• CELL BIOLOGY
• MITOCHONDRIA
• AUTOPHAGY
• PARKIN
• UBIQUITIN
• RAB7

詳細情報

• CRID: 1050282810834094720
• NII論文ID: 120006457172
• ISSN: 2050084X
• DOI: 10.7554/elife.31326
• HANDLE: 2433/230629
• Web Site: https://cdn.elifesciences.org/articles/31326/elife-31326-v1.pdf
• Web Site: https://cdn.elifesciences.org/articles/31326/elife-31326-v1.xml
• Web Site: https://elifesciences.org/articles/31326
• 本文言語コード: en
• 資料種別: journal article
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