Regulation of Autophagy Enzymes by Nutrient Signaling

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) 2021-08, Vol.46 (8), p.687-700
• Main Authors: King, Karyn E., Losier, Truc T., Russell, Ryan C.
• Format: Article
• Language: English
• Subjects: amino acids; AMPK; ATG complexes; glucose; mTORC1; oxygen
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2021.01.006

Autophagy is the primary catabolic program of the cell that promotes survival in response to metabolic stress. It is tightly regulated by a suite of kinases responsive to nutrient status, including mammalian target of rapamycin complex 1 (mTORC1), AMP-activated protein kinase (AMPK), protein kinase C-α (PKCα), MAPK-activated protein kinases 2/3 (MAPKAPK2/3), Rho kinase 1 (ROCK1), c-Jun N-terminal kinase 1 (JNK), and Casein kinase 2 (CSNK2). Here, we highlight recently uncovered mechanisms linking amino acid, glucose, and oxygen levels to autophagy regulation through mTORC1 and AMPK. In addition, we describe new pathways governing the autophagic machinery, including the Unc-51-like (ULK1), vacuolar protein sorting 34 (VPS34), and autophagy related 16 like 1 (ATG16L1) enzyme complexes. Novel downstream targets of ULK1 protein kinase are also discussed, such as the ATG16L1 subunit of the microtubule-associated protein 1 light chain 3 (LC3)-lipidating enzyme and the ATG14 subunit of the VPS34 complex. Collectively, we describe the complexities of the autophagy pathway and its role in maintaining cellular nutrient homeostasis during times of starvation. Autophagy is the primary degradative program of the cell that provides essential macromolecular building blocks to fuel biosynthetic pathways during times of nutrient deprivation.Recruitment of the LC3-lipidating enzyme to maturing autophagosomes is regulated by both VPS34-mediated phospholipid production and the ULK1 complex.Changes in amino acid, glucose, and oxygen levels are sensed by stress-sensitive kinases mTORC1 and AMPK and control autophagy through distinct but strikingly similar downstream targets.Recent advances revealed new pathways regulating the stability and activity of the core autophagic machinery in response to nutrient status, including the ULK1, VPS34, and ATG16L1 enzyme complexes.The most upstream enzyme in the autophagy pathway, ULK1 protein kinase, directly phosphorylates several autophagy proteins under starvation, including the VPS34 and ATG16L1 complexes, to promote autophagy.