ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy.
Autophagy is a degradative process that recycles long-lived and faulty cellular components. It is linked to many diseases and is required for normal development. ULK1, a mammalian serine/threonine protein kinase, plays a key role in the initial stages of autophagy, though the exact molecular mechanism is unknown. Here we report identification of a novel protein complex containing ULK1 and two additional protein factors, FIP200 and ATG13, all of which are essential for starvation-induced autophagy. Both FIP200 and ATG13 are critical for correct localization of ULK1 to the pre-autophagosome and stability of ULK1 protein. Additionally, we demonstrate by using both cellular experiments and a de novo in vitro reconstituted reaction that FIP200 and ATG13 can enhance ULK1 kinase activity individually but both are required for maximal stimulation. Further, we show that ATG13 and ULK1 are phosphorylated by the mTOR pathway in a nutrient starvation-regulated manner, indicating that the ULK1.ATG13.FIP200 complex acts as a node for integrating incoming autophagy signals into autophagosome biogenesis.
Ganley
Ian G
IG
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Lam
Du H
du H
Wang
Junru
J
Ding
Xiaojun
X
Chen
She
S
Jiang
Xuejun
X
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases
C534291:ATG13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; C407704:RB1CC1 protein, human; C428743:Rb1cc1 protein, mouse; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D011505:Protein-Tyrosine Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; C112444:Ulk1 protein, mouse