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Originally published In Press as doi:10.1074/jbc.C000752200 on November 28, 2000

J. Biol. Chem., Vol. 276, Issue 3, 1701-1706, January 19, 2001
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The Human Homolog of Saccharomyces cerevisiae Apg7p Is a Protein-activating Enzyme for Multiple Substrates Including Human Apg12p, GATE-16, GABARAP, and MAP-LC3*

Isei Tanida, Emiko Tanida-Miyake, Takashi Ueno, and Eiki KominamiDagger

From the Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan

Autophagy is a process that involves the bulk degradation of cytoplasmic components by the lysosomal/vacuolar system. In the yeast, Saccharomyces cerevisiae, an autophagosome is formed in the cytosol. The outer membrane of the autophagosome is fused with the vacuole, releasing the inner membrane structure, an autophagic body, into the vacuole. The autophagic body is subsequently degraded by vacuolar hydrolases. Taking advantage of yeast genetics, apg (autophagy-defective) mutants were isolated that are defective in terms of formation of autophagic bodies under nutrient starvation conditions. One of the APG gene products, Apg12p, is covalently attached to Apg5p via the C-terminal Gly of Apg12p as in the case of ubiquitylation, and this conjugation is essential for autophagy. Apg7p is a novel E1 enzyme essential for the Apg12p-conjugation system. In mammalian cells, the human Apg12p homolog (hApg12p) also conjugates with the human Apg5p homolog. In this study, the unique characteristics of hApg7p are shown. A two-hybrid experiment indicated that hApg12p interacts with hApg7p. Site-directed mutagenesis revealed that Cys572 of hApg7p is an authentic active site cysteine residue essential for the formation of the hApg7p·hApg12p intermediate. Overexpression of hApg7p enhances the formation of the hApg5p·hApg12p conjugate, indicating that hApg7p is an E1-like enzyme essential for the hApg12p conjugation system. Cross-linking experiments and glycerol-gradient centrifugation analysis showed that the mammalian Apg7p homolog forms a homodimer as in yeast Apg7p. Each of three human Apg8p counterparts, i.e. the Golgi-associated ATPase enhancer of 16 kDa, GABAA receptor-associated protein, and microtubule-associated protein light chain 3, coimmunoprecipitates with hApg7p and conjugates with mutant hApg7pC572S to form a stable intermediate via an ester bond. These results indicate that hApg7p is an authentic protein-activating enzyme for hApg12p and the three Apg8p homologs.

* This work was supported in part by Grants-in-aid 12780543 (to I. T.), 09680629 (to T. U.), and 12470040 (to E. K.) for Scientific Research, Grants-in-aid 12146205 (to E. K.) for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture of Japan, and The Science Research Promotion Fund from the Japan Private School Promotion Foundation (to E. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Biochemistry, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Tel.: 81-3-5802-1031; Fax: 81-3-5802-5889; E-mail: kominami@med.juntendo.ac.jp.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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