ULK1·ATG13·FIP200 Complex Mediates mTOR Signaling and Is Essential for Autophagy*

By I. Ganley, Du Lam, Junru Wang, Xiaojun Ding, She Chen, Xuejun Jiang. Journal of Biological Chemistry, 2009

1,494 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/55593f933e6aa4d113aaa30923460f12ad794ffb

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Citations in the corpus

mTOR regulation of autophagy (2010, background): “Indeed, mTORC1 regulated the kinase activity of ULK1 and ULK2 [64,66,71,72] (Fig.”
Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks (2011, background): “The product of the mammalian C12orf44 gene has been identified as an additional component of the Ulk1/2-Atg13FIP200 complex and as direct binding partner of Atg13 (38, 78).”
Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells (2011, background): “ATG13.”
mTOR: a pharmacologic target for autophagy regulation. (2015, neutral): “In yeast, TORC1 inhibits the autophagy-initiating kinase ATG1 (the mammalian ULK1/2 homolog) by phosphorylating ATG13 and disrupting the ATG1 and ATG13 interaction (69).”
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “Nilotinib, a c-Abl kinase inhibitor and AMPK activator (Yu et al., 2013), was shown to induce autophagy and ameliorate disease phenotype in PD mice (Hebron et al., 2014; Lonskaya et al., 2015).”
Recent insights into the function of autophagy in cancer (2016, background): “Regulation of core autophagy genes and cargo receptors in cancer The first complex known to regulate autophagy is the ULK1–ATG13–FIP200 complex (Ganley et al. 2009).”