@article{99542e3e8fab465b80e8d4ee9862be6e,
title = "TOM40 Targets Atg2 to Mitochondria-Associated ER Membranes for Phagophore Expansion",
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.",
author = "Zhenyuan Tang and Yoshinori Takahashi and Haiyan He and Tatsuya Hattori and C. Chen and Xinwen Liang and Han Chen and Young, {Megan M.} and Wang, {Hong Gang}",
note = "Funding Information: This work was supported by the NIH grants GM127954 and CA222349, the Hyundai Hope On Wheels, the Four Diamonds, and the Lois High Berstler Research Endowment Fund. Authors would like to thank Nate Sheaffer, Joseph Bednarczyk, and Jade Vogel from the Penn State College of Medicine Flow Cytometry Core for assistance with the flow cytometry; Thomas Abraham and Wade Edris of the Penn State College of Medicine Imaging Core for assistance with the confocal microscopy; and Haiyan Zheng of the Rutgers University Biological Mass Spectrometry Facility for assistance with the proteomic analysis. Z.T. and Y.T. performed the experiments and analyzed the data; H.H. T.H. C.C. H.C. X.L. and M.M.Y. assisted in collecting and analyzing the data and preparing the manuscript; Z.T. Y.T. M.M.Y. and H.-G.W. designed the experiments, discussed the results, and wrote the manuscript. The authors declare no competing interests. Funding Information: This work was supported by the NIH grants GM127954 and CA222349 , the Hyundai Hope On Wheels , the Four Diamonds , and the Lois High Berstler Research Endowment Fund. Authors would like to thank Nate Sheaffer, Joseph Bednarczyk, and Jade Vogel from the Penn State College of Medicine Flow Cytometry Core for assistance with the flow cytometry; Thomas Abraham and Wade Edris of the Penn State College of Medicine Imaging Core for assistance with the confocal microscopy; and Haiyan Zheng of the Rutgers University Biological Mass Spectrometry Facility for assistance with the proteomic analysis. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = aug,
day = "13",
doi = "10.1016/j.celrep.2019.07.036",
language = "English (US)",
volume = "28",
pages = "1744--1757.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}