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Vol. 19, Issue 12, 5506-5516, December 2008

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Self-Interaction Is Critical for Atg9 Transport and Function at the Phagophore Assembly Site during Autophagy

Congcong He^*, Misuzu Baba, Yang Cao^*, and Daniel J. Klionsky^*

*Life Sciences Institute and Departments of Molecular, Cellular and Developmental Biology, and Biological Chemistry, University of Michigan, Ann Arbor, MI 48109; and Department of Chemical and Biological Sciences, Faculty of Science, Japan Women's University, Mejirodai, Tokyo 112-8681, Japan

Submitted May 30, 2008; Revised September 22, 2008; Accepted September 23, 2008
Monitoring Editor: Jeffrey L. Brodsky

Autophagy is the degradation of a cell's own components within lysosomes (or the analogous yeast vacuole), and its malfunction contributes to a variety of human diseases. Atg9 is the sole integral membrane protein required in formation of the initial sequestering compartment, the phagophore, and is proposed to play a key role in membrane transport; the phagophore presumably expands by vesicular addition to form a complete autophagosome. It is not clear through what mechanism Atg9 functions at the phagophore assembly site (PAS). Here we report that Atg9 molecules self-associate independently of other known autophagy proteins in both nutrient-rich and starvation conditions. Mutational analyses reveal that self-interaction is critical for anterograde transport of Atg9 to the PAS. The ability of Atg9 to self-interact is required for both selective and nonselective autophagy at the step of phagophore expansion at the PAS. Our results support a model in which Atg9 multimerization facilitates membrane flow to the PAS for phagophore formation.

Address correspondence to: Daniel J. Klionsky (klionsky{at}umich.edu).

Abbreviations used: Ape1, aminopeptidase I; Atg, autophagy-related; Cvt, cytoplasm to vacuole targeting; MKO, multiple-knockout; PAS, phagophore assembly site; prApe1, precursor aminopeptidase I; SNARE, N-ethylmaleimide-sensitive factor attachment protein receptor.

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