Feedback on fat: p62-mTORC1-autophagy connections

Abstract

Metabolic homeostasis requires integration of multiple signals and cellular activities. Without this integration, conditions of obesity and diabetes often develop. Recent in vivo studies explore the molecular basis for metabolic homestasis, showing that p62 links autophagy and mTORC1 activation to regulate adipogenesis and energy control.

Figure 1. Role of p62 in autophagy and mTORC1 regulation

(A) Domain organization and interacting partners of p62. PB1, Phox/Bem domain 1, interacts with ERK1 to control adipogenesis and, with aPKCs, to control NF-κB; the interaction with NBR1 is also through the PB1 but its role needs to be clarified. ZZ, atypical zinc-finger, governs the interaction with RIP and might be relevant for TNFα-activated NF-κB. TB, TRAF6-binding, accounts for p62’s role in IL-1, NGF and RANK towards NF-κB. LIR, LC3-interacting region, locates p62 in the autophagosomes; KIR, Keap-interacting region, serves to regulate NRF2 activation; UBA, ubiquitin-associated, mediates the interaction with poly-ubiquitinated proteins, including caspase-8, and modulates TRAF6 interaction and activity. (B) p62 senses nutrient signals and activates mTORC1, inhibiting autophagy and creating a loop that results in enhanced p62 levels. (C) During senescence and lysosomal biogenesis, p62 and mTORC1 are most likely separated from the autophagosome, which generates amino acids that can, in turn, regulate mTORC1 activation. (D) High-calorie diets promote lipogenesis and adiposity through mTORC1 activation, which is antagonized by p62. p62, itself, is modulated by autophagy and that likely controls the anti-inflammatory actions of PKCζ.