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Vol. 19, Issue 11, 4762-4775, November 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-03-0309v1 19/11/4762    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sou, Y.-s. Articles by Komatsu, M. PubMed PubMed Citation Articles by Sou, Y.-s. Articles by Komatsu, M.

The Atg8 Conjugation System Is Indispensable for Proper Development of Autophagic Isolation Membranes in Mice

Yu-shin Sou^*,,, Satoshi Waguri^,, Jun-ichi Iwata^*,,, Takashi Ueno^,||, Tsutomu Fujimura^||, Taichi Hara^¶, Naoki Sawada, Akane Yamada, Noboru Mizushima^¶,#, Yasuo Uchiyama^@, Eiki Kominami, Keiji Tanaka^*, and Masaaki Komatsu^*,,**

*Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan; Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Anatomy and Histology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; ^||Division of Proteomics and Biomolecular Science, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan; ^¶Department of Physiology and Cell Biology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Bunkyo-ku, Tokyo 113-8519, Japan; ^#SORST, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan; ^@Department of Anatomy, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan; and **PRESTO, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan

Submitted March 25, 2008; Revised August 19, 2008; Accepted August 22, 2008
Monitoring Editor: Suresh Subramani

Autophagy is an evolutionarily conserved bulk-protein degradation pathway in which isolation membranes engulf the cytoplasmic constituents, and the resulting autophagosomes transport them to lysosomes. Two ubiquitin-like conjugation systems, termed Atg12 and Atg8 systems, are essential for autophagosomal formation. In addition to the pathophysiological roles of autophagy in mammals, recent mouse genetic studies have shown that the Atg8 system is predominantly under the control of the Atg12 system. To clarify the roles of the Atg8 system in mammalian autophagosome formation, we generated mice deficient in Atg3 gene encoding specific E2 enzyme for Atg8. Atg3-deficient mice were born but died within 1 d after birth. Conjugate formation of mammalian Atg8 homologues was completely defective in the mutant mice. Intriguingly, Atg12–Atg5 conjugation was markedly decreased in Atg3-deficient mice, and its dissociation from isolation membranes was significantly delayed. Furthermore, loss of Atg3 was associated with defective process of autophagosome formation, including the elongation and complete closure of the isolation membranes, resulting in malformation of the autophagosomes. The results indicate the essential role of the Atg8 system in the proper development of autophagic isolation membranes in mice.

These authors contributed equally to this work.

Address correspondence to: Masaaki Komatsu (komatsu-ms{at}igakuken.or.jp)

Abbreviations used: BCAA, branched chain amino acids; ES, embryonic stem; GABARAP, GABA(A) receptor-associated protein; GATE-16, Golgi-associated ATPase enhancer of 16 kDa; GFP, green fluorescent protein; LC3, microtubule-associated protein 1 light chain 3/MAP1LC3; MEF, mouse embryonic fibroblasts; PE, phosphatidylethanolamine.