TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion

Zhenyuan Tang, Yoshinori Takahashi, Haiyan He, Tatsuya Hattori, C. Chen, Xinwen Liang, Han Chen, Megan M. Young, Hong Gang Wang

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

During autophagy, phagophores grow into double-membrane vesicles called autophagosomes, but the underlying mechanism remains unclear. Here, we show a critical role of Atg2A in phagophore expansion. Atg2A translocates to the phagophore at the mitochondria-associated ER membrane (MAM) through a C-terminal 45-amino acid domain that we have termed the MAM localization domain (MLD). Proteomic analysis identifies the outer mitochondrial membrane protein TOM40 as a MLD-interacting partner. The Atg2A-TOM40 interaction is responsible for MAM localization of Atg2A and requires the TOM receptor protein TOM70. In addition, Atg2A interacts with Atg9A by a region within its N terminus. Inhibition of either Atg2A-TOM40 or Atg2A-Atg9A interactions impairs phagophore expansion and accumulates Atg9A-vesicles in the vicinity of autophagic structures. Collectively, we propose a model that the TOM70-TOM40 complex recruits Atg2A to the MAM for vesicular and/or non-vesicular lipid transport into the expanding phagophore to grow the size of autophagosomes for efficient autophagic flux. Tang et al. show that human Atg2 is a key regulator for phagophore expansion. TOM40/70 directs Atg2A to MAM to mediate phagophore expansion. On the MAM, Atg2A facilitates Atg9-vesicle delivery and retrograde trafficking to promote phagophore expansion and efficient autophagic flux.

Original languageEnglish (US)
Pages (from-to)1744-1757.e5
JournalCell Reports
Volume28
Issue number7
DOIs
StatePublished - Aug 13 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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