p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway

Abstract

SUMMARY The signaling adapter p62 is a critical mediator of important cellular functions owing to its ability to establish interactions with various signaling intermediaries. Here we identify raptor as an interacting partner of p62. Thus, p62 is an integral part of the mTORC1 complex, and is necessary to mediate amino acid signaling for the activation of S6K1 and 4EBP1. p62 interacts in an amino acid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags proteins and favors formation of the active Rag heterodimer that is further stabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo, and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation.

p62/SQSTM1 at the interface of aging, autophagy, and disease

“…Amino acid levels are linked to mTOR through a mechanism that is dependent, at least to some extent, on p62/ SQSTM1 (Duran et al 2011): mTORC1 associates with the amino acid sensing Rag family of small GTPases (Kim et al 2008;Sancak et al 2008) on the surface of lysosomes (Sancak et al 2010). p62/SQSTM1 mediates this process by associating with Raptor, a subunit of the mTORC1 complex, and the Rag GTPases, thereby forming a high molecular weight complex that relays the signal from amino acids to the mTORC1 pathway (Duran et al 2011).…”

“…p62/SQSTM1 mediates this process by associating with Raptor, a subunit of the mTORC1 complex, and the Rag GTPases, thereby forming a high molecular weight complex that relays the signal from amino acids to the mTORC1 pathway (Duran et al 2011). Although the physiological role of this interaction has not been defined, it is possible that the p62/SQSTM1-mTORC1 complex responds locally to amino acids produced by the autophagy-lysosome system to prevent excessive autophagy.…”

“…It must be noted that, while mTORC1 is activated by many different inputs, the regulation through amino acid levels is currently the only input known to require p62/SQSTM1. Insulin, for example, can activate mTORC1 in the absence of p62/ SQSTM1 (Duran et al 2011). Furthermore, p62/ SQSTM1 knockdown elicits autophagy in ways that are reminiscent of amino acid starvation (Duran et al 2011).…”

“…Insulin, for example, can activate mTORC1 in the absence of p62/ SQSTM1 (Duran et al 2011). Furthermore, p62/ SQSTM1 knockdown elicits autophagy in ways that are reminiscent of amino acid starvation (Duran et al 2011). Thus, p62/SQSTM1 levels may serve as a rheostat to sense free amino acid availability in the cell, turning on anabolic pathways through mTORC1 when amino acids are abundant, and shutting them down when there are insufficient nutrients for protein synthesis.…”

“…The mTORC1 pathway is also responsible for peripheral resistance to insulin: increasing the activity of S6K1, a mTORC1 substrate, can trigger a negative feedback on the insulin receptor substrate 1 (IRS-1), thereby impairing insulin signaling (Um et al 2004). mTORC1 response to insulin is independent of p62/ SQSTM1 (Duran et al 2011) and the insulin signaling pathway is not impaired in young Sqstm1 −/− mice (Rodriguez et al 2006). Nevertheless, p62/SQSTM1 may help modulating the response to insulin by sequestering mTORC1 into insulin-insensitive, amino acidresponsive complexes, thereby reducing S6K1 activation and the negative feedback on IRS-1, when the adipocytes are excessively stimulated.…”