ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase

By R. Russell, Ye Tian, Hai‐Xin Yuan, H. Park, Yu-Yun Chang, Joungmok Kim, Haerin Kim, T. P. Neufeld, A. Dillin, K. Guan. Nature Cell Biology, 2013

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Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction.

Subfields: Cell Biology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/20c3c5842114d9884de31bcd4649949e51b02211

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Citations in the corpus

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “This BECN1 phosphorylation by ULK1 is required for full autophagic induction.(494) In addition, ULK1 binds to, and phosphorylates, RPTOR, leading to inhibition of MTORC1.”
Molecular definitions of autophagy and related processes (2017, positive): “In mammalian cells, ULK1 directly phosphorylates BECN1, resembling AMPK in its VPS34-stimulatory effects (Russell et al , 2013), and ATG14 (Park et al , 2016; Wold et al , 2016).”
To be or not to be? How selective autophagy and cell death govern cell fate. (2014, positive): “The Class III PI3K complex generates PI3P at the site of nucleation of the isolation membrane (also known as the phagophore), which leads to the binding of PI3P-binding proteins (such as WIPI/II) and the subsequent recruitment of proteins involved in the ''elongation reaction'' (also called the ubiq”
Recent insights into the function of autophagy in cancer (2016, background): “The most characterized of these started with a FAK inhibitor that potently inhibited ULK1 function (Russell et al. 2013; Egan et al. 2015).”
Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. (2014, background): “ULK1 directly phosphorylates it and activates hVPS34 in response to mammalian TOR (mTOR) inhibition (Russell et al., 2013).”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “158,159 The mTORC1 and AMPK control the activity of the VPS34 complex which is needed for the generation of the autophagosome.”
Autophagy during viral infection — a double-edged sword (2018, background): “Nutrient starvation or rapamycin, which is an mToRC1 inhibitor, induces the formation of the active ulK1 complex, which ultimately phosphorylates and activates the Beclin 1-vPS34 complex 152, 153 .”
Mechanisms of Autophagy Initiation (2017, background): “ULK1 activates PI3KC3-C1 by phosphorylating BECN1 at Ser15 (73).”
Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates (2015, background): “It is notable, however, that mTORC1 is inactivated by many stresses beyond just those affecting AMPK, and the data to date suggest that pharmacological suppression of mTORC1 is sufficient to induce ULK1 kinase activity (Russell et al., 2013).”
Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “, 2017), Beclin 1 (BECN1; a mammalian homolog of yeast Vps30/Atg6) (Park et al., 2018; Russell et al., 2013), and autophagy and beclin 1 regulator 1 (AMBRA1) (Russell et al.”