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 language | English (US) |
|---|---|
| Pages (from-to) | 1744-1757.e5 |
| Journal | Cell Reports |
| Volume | 28 |
| Issue number | 7 |
| DOIs | |
| State | Published - Aug 13 2019 |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
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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 journal › Article
TY - JOUR
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
PY - 2019/8/13
Y1 - 2019/8/13
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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U2 - 10.1016/j.celrep.2019.07.036
DO - 10.1016/j.celrep.2019.07.036
M3 - Article
C2 - 31412244
AN - SCOPUS:85069941087
VL - 28
SP - 1744-1757.e5
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 7
ER -