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Vol. 19, Issue 5, 2092-2100, May 2008

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The Atg16L Complex Specifies the Site of LC3 Lipidation for Membrane Biogenesis in Autophagy

Naonobu Fujita^*,, Takashi Itoh, Hiroko Omori^*, Mitsunori Fukuda, Takeshi Noda^*, and Tamotsu Yoshimori^*,

*Department of Cellular Regulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan; Department of Genetics, The Graduate University for Advanced Studies, Mishima 455-8540, Japan; Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Miyagi 980-8578, Japan; and CREST, Japan Science and Technology Agency, Kawaguchi-Saitama 332-0012, Japan

Submitted December 18, 2007; Revised February 14, 2008; Accepted February 25, 2008
Monitoring Editor: Howard Riezman

Two ubiquitin-like molecules, Atg12 and LC3/Atg8, are involved in autophagosome biogenesis. Atg12 is conjugated to Atg5 and forms an 800-kDa protein complex with Atg16L (referred to as Atg16L complex). LC3/Atg8 is conjugated to phosphatidylethanolamine and is associated with autophagosome formation, perhaps by enabling membrane elongation. Although the Atg16L complex is required for efficient LC3 lipidation, its role is unknown. Here, we show that overexpression of Atg12 or Atg16L inhibits autophagosome formation. Mechanistically, the site of LC3 lipidation is determined by the membrane localization of the Atg16L complex as well as the interaction of Atg12 with Atg3, the E2 enzyme for the LC3 lipidation process. Forced localization of Atg16L to the plasma membrane enabled ectopic LC3 lipidation at that site. We propose that the Atg16L complex is a new type of E3-like enzyme that functions as a scaffold for LC3 lipidation by dynamically localizing to the putative source membranes for autophagosome formation.

Address correspondence to: Tamotsu Yoshimori (tamyoshi{at}biken.osaka-u.ac.jp).

Abbreviations used: HBSS, Hanks' balanced salt solution; PE, phosphatidylethanolamine; PI3K, phosphatidylinositol 3-kinase; PM, plasma membrane.

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