K63 Polyubiquitination and Activation of mTOR by the p62-TRAF6 Complex in Nutrient-Activated Cells

Abstract

SUMMARY The ability of cells to respond to changes in nutrient availability is critical for an adequate control of metabolic homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is a central complex kinase in these processes. The signaling adaptor p62 binds raptor, and integral component of the mTORC1 pathway. p62 interacts with TNF receptor associated factor 6 (TRAF6) and is required for mTORC1 translocation to the lysosome and its subsequent activation. Here we show that TRAF6 is recruited to and activates mTORC1 through p62 in amino acid-stimulated cells. We also show that TRAF6 is necessary for the translocation of mTORC1 to the lysosomes and that the TRAF6-catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids. TRAF6, through its interaction with p62 and activation of mTORC1, modulates autophagy and is an important mediator in cancer cell proliferation. Interfering with the p62-TRAF6 interaction serves to modulate autophagy and nutrient sensing.

TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis

“…Degradation of p62-bound polyubiquitinated proteins within autophagosomes is mediated by autophagy (22). The decrease in autophagy in Tak1 -/-hepatocytes results in accumulation of p62, which leads to further activation of mTORC1, as recently described (36,37). The decrease in autophagy and the increase in mTORC1 activity resulted in enhanced development of hepatosteatosis in HFD-fed Tak1…”

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

“…(Scale bar, 10 μm.) adaptor protein that can form distinct signal-organizing nodes modulating the cellular response to stimuli such as cytokines or amino acids (35)(36)(37). Central to its role as a signal rheostat is the ability of p62 to solicit ubiquitin E3 ligases to p62-orchestrated signaling hubs (38).…”

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

“…In response to nutrients, p62 brings TRAF6 to mTORC1 via its binding affinity for both raptor and TRAF6. 56 Then, the recruited TRAF6 marks mTOR with K63-linked ubiquitin chains, which are instrumental for the activation of mTOR. In addition, K48-linked ubiquitination has been documented to directly affect the stability or indirectly affect Figure 3 The ubiquitin system regulates the xenophagy of bacterial pathogens.…”