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doi: 10.1242/10.1242/jcs.00381


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Journal of Cell Science 116, 1679-1688 (2003)
doi: 10.1242/jcs.00381


Research Article

Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate

Noboru Mizushima1,2,*, Akiko Kuma2,3, Yoshinori Kobayashi2,3, Akitsugu Yamamoto4, Masami Matsubae5, Toshifumi Takao5, Tohru Natsume6, Yoshinori Ohsumi2,3,* and Tamotsu Yoshimori2,3,7

1 PRESTO, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan
2 Department of Cell Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Japan
3 Department of Molecular Biomechanics, School of Life Science, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan
4 Department of Physiology, Kansai Medical University, Moriguchi 570-8506, Japan
5 Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan
6 National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
7 Department of Cell Genetics, National Institute of Genetics, Mishima 411-8540, Japan

* Authors for correspondence (e-mail: nmizu{at}nibb.ac.jp; yohsumi{at}nibb.ac.jp)

Accepted 21 January 2003

Macroautophagy is the major intracellular degradation system delivering cytoplasmic components to the lysosome/vacuole. We have shown that, in yeast and mammalian cells, the Apg12-Apg5 protein conjugate, which is formed by a ubiquitin-like system, is essential for autophagosome formation. In yeast, the Apg12-Apg5 conjugate interacts with a small coiled-coil protein, Apg16, to form a ~350 kDa multimeric complex. We demonstrate that the mouse Apg12-Apg5 conjugate forms a ~800 kDa protein complex containing a novel WD-repeat protein. Because the N-terminal region of this novel protein shows homology with yeast Apg16, we have designated it mouse Apg16-like protein (Apg16L). Apg16L, however, has a large C-terminal domain containing seven WD repeats that is absent from yeast Apg16. Apg16L interacts with both Apg5 and additional Apg16L monomers; neither interaction, however, depends on the WD-repeat domain. In conjunction with Apg12-Apg5, Apg16L associates with the autophagic isolation membrane for the duration of autophagosome formation. Because these features are similar to yeast Apg16, we concluded Apg16L is the functional counterpart of the yeast Apg16. We also found that membrane targeting of Apg16L requires Apg5 but not Apg12. Because WD-repeat proteins provide a platform for protein-protein interactions, the ~800 kDa complex is expected to function in autophagosome formation, further interacting with other proteins in mammalian cells.

Key words: Autophagy, Apg12, Apg5, WD repeat




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