FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells.
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.
Hara
Taichi
T
Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan.
Takamura
Akito
A
Kishi
Chieko
C
Iemura
Shun-Ichiro
S
Natsume
Tohru
T
Guan
Jun-Lin
JL
Mizushima
Noboru
N
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D005656:Fungal Proteins; D008869:Microtubule-Associated Proteins; C407704:RB1CC1 protein, human; D011993:Recombinant Fusion Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C401061:Ulk2 protein, mouse; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse