Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy

Yansheng Ye, Erin R. Tyndall, Bui Van, Maria C. Bewley, Guifang Wang, Xupeng Hong, Yang Shen, John M. Flanagan, Hong-Gang Wang () and Fang Tian ()
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Yansheng Ye: Pennsylvania State University College of Medicine
Erin R. Tyndall: Pennsylvania State University College of Medicine
Bui Van: Pennsylvania State University College of Medicine
Maria C. Bewley: Pennsylvania State University College of Medicine
Guifang Wang: Pennsylvania State University College of Medicine
Xupeng Hong: Pennsylvania State University College of Medicine
Yang Shen: US National Institutes of Health
John M. Flanagan: Pennsylvania State University College of Medicine
Hong-Gang Wang: Pennsylvania State University College of Medicine
Fang Tian: Pennsylvania State University College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Autophagosome formation, a crucial step in macroautophagy (autophagy), requires the covalent conjugation of LC3 proteins to the amino headgroup of phosphatidylethanolamine (PE) lipids. Atg3, an E2-like enzyme, catalyzes the transfer of LC3 from LC3-Atg3 to PEs in targeted membranes. Here we show that the catalytically important C-terminal regions of human Atg3 (hAtg3) are conformationally dynamic and directly interact with the membrane, in collaboration with its N-terminal membrane curvature-sensitive helix. The functional relevance of these interactions was confirmed by in vitro conjugation and in vivo cellular assays. Therefore, highly curved phagophoric rims not only serve as a geometric cue for hAtg3 recruitment, but also their interaction with hAtg3 promotes LC3-PE conjugation by targeting its catalytic center to the membrane surface and bringing substrates into proximity. Our studies advance the notion that autophagosome biogenesis is directly guided by the spatial interactions of Atg3 with highly curved phagophoric rims.

Date: 2023
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DOI: 10.1038/s41467-023-41243-4

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