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Published online April 28, 2008
doi:10.1083/jcb.200712064
The Journal of Cell Biology, Vol. 181, No. 3, 497-510
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Hara et al.
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Article

 FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells

Taichi Hara1, Akito Takamura1, Chieko Kishi1, Shun-ichiro Iemura2, Tohru Natsume2, Jun-Lin Guan3, and Noboru Mizushima1,4

1 Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan
2 Biological Information Research Center, National Institutes of Advanced Industrial Science and Technology, Kohtoh-ku, Tokyo 135-0064, Japan
3 Department of Internal Medicine-MMG, University of Michigan Medical School, Ann Arbor, MI 48109
4 Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Correspondence to Noboru Mizushima: nmizu.phy2{at}tmd.ac.jp

Autophagy is a membrane-mediated intracellular degradation system. The serine/threonine kinase Atg1 plays an essential role in autophagosome formation. However, the role of the mammalian Atg1 homologues UNC-51–like kinase (ULK) 1 and 2 are not yet well understood. We found that murine ULK1 and 2 localized to autophagic isolation membrane under starvation conditions. Kinase-dead alleles of ULK1 and 2 exerted a dominant-negative effect on autophagosome formation, suggesting that ULK kinase activity is important for autophagy. We next screened for ULK binding proteins and identified the focal adhesion kinase family interacting protein of 200 kD (FIP200), which regulates diverse cellular functions such as cell size, proliferation, and migration. We found that FIP200 was redistributed from the cytoplasm to the isolation membrane under starvation conditions. In FIP200-deficient cells, autophagy induction by various treatments was abolished, and both stability and phosphorylation of ULK1 were impaired. These results suggest that FIP200 is a novel mammalian autophagy factor that functions together with ULKs.

Abbreviations used in this paper: Cvt, cytoplasm-to-vacuole targeting; E, embryonic day; FIP200, FAK family–interacting protein of 200 kD; MEF, mouse embryonic fibroblast; mTOR, mammalian target of rapamycin; PAS, preautophagosomal structure; PE, phosphatidylethanolamine; ULK, UNC-51–like kinase.


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