Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy

By Joungmok Kim, Young Chul Kim, C. Fang, R. Russell, Jeong Hee Kim, Weiliang Fan, Rong Liu, Q. Zhong, K. Guan. Cell, 2013

789 citations recorded by the source corpus.

Summary Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the non-autophagy Vps34 complex by phosphorylating T163/S165 in Vps34, therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the pro-autophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy essential gene present only in pro-autophagy Vps 34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy.

Subfields: Cell Biology, Epidemiology, Surgery

View Paper: https://www.semanticscholar.org/paper/0ec3c872ed4f561c09eb36544e3fd512d1e3733f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. N. Mizushima
2. Beth Levine
3. I. Slaninová
4. D. Klionsky
5. V. Deretic
6. Guido Kroemer
7. Douglas R. Green
8. Alec C. Kimmelman

In Epidemiology

1. Beth Levine
2. Guido Kroemer
3. N. Mizushima
4. I. Slaninová
5. D. Klionsky
6. V. Deretic
7. Douglas R. Green
8. Alec C. Kimmelman

In Surgery

1. Young Chul Kim
2. Alec C. Kimmelman
3. K. Guan
4. N. Mizushima
5. V. Deretic
6. R. Shaw
7. Beth Levine
8. Guido Kroemer

Citations in the corpus

• Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates (2015, background): “Recent reports that AMPK phosphorylates Beclin1 and Vps34 on distinct sites from these ULK1 sites (Kim et al., 2013) and that the stress-induced MK2/MK3 kinases also target additional sites in Beclin1 (Wei et al.”
• mTOR: a pharmacologic target for autophagy regulation. (2015, positive): “Therefore, since active AMPK promotes autophagy by phosphorylating key autophagy regulatory proteins such as ULK1, VPS34, and Beclin 1 (70, 72), metformin can induce autophagy by simultaneously activating AMPK and inhibiting mTORC1.”
• To be or not to be? How selective autophagy and cell death govern cell fate. (2014, neutral): “1/VPS34 complex (Kim et al., 2013a).”
• ULK1 induces autophagy by phosphorylating Beclin-1 and activating Vps34 lipid kinase (2013, methodology): “Active GST-ULK1 (1-649) and GST-ULK2 (1-478) from insect cells was purchased from CQuential Solutions (Moraga, CA).”
• Molecular definitions of autophagy and related processes (2017, positive): “The existence of ATG3-, ATG5-, ATG7-, ULK1-, BECN1-, VPS34-, and PI3P-independent forms of macroautophagy lent further support to the hypothesis that the molecular mechanisms underlying macroautophagic responses exhibit considerable degree of redundancy (at least in mammals) (Nishida et al , 2009; C”