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 Marie Young, Hong-Gang Wang

Research output: Contribution to journalArticle

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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

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Mitochondria
Membranes
Fluxes
Mitochondrial Proteins
Autophagy
Mitochondrial Membranes
Proteomics
Membrane Proteins
Lipids
Amino Acids

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Tang, Zhenyuan ; Takahashi, Yoshinori ; He, Haiyan ; Hattori, Tatsuya ; Chen, C. ; Liang, Xinwen ; Chen, Han ; Young, Megan Marie ; Wang, Hong-Gang. / TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion. In: Cell Reports. 2019 ; Vol. 28, No. 7. pp. 1744-1757.e5.
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TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion. / Tang, Zhenyuan; Takahashi, Yoshinori; He, Haiyan; Hattori, Tatsuya; Chen, C.; Liang, Xinwen; Chen, Han; Young, Megan Marie; Wang, Hong-Gang.

In: Cell Reports, Vol. 28, No. 7, 13.08.2019, p. 1744-1757.e5.

Research output: Contribution to journalArticle

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T1 - TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion

AU - Tang, Zhenyuan

AU - Takahashi, Yoshinori

AU - He, Haiyan

AU - Hattori, Tatsuya

AU - Chen, C.

AU - Liang, Xinwen

AU - Chen, Han

AU - Young, Megan Marie

AU - Wang, Hong-Gang

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N2 - 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.

AB - 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.

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