The signaling adaptor 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.
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► p62 is a component of mTORC1 complex and not mTORC2 via interaction with raptor ► p62 is required for mTORC1 activation in response to amino acids ► p62 interacts with the Rag GTPases and induces the formation of the active Rag dimer ► p62 mediates mTORC1 recruitment to lysosomes
Adaptor proteins participate in selective autophagy, which is critical for cellular detoxification and stress relief. However, new evidence supports an autophagy-independent key role of the adaptor ...p62 (encoded by the gene Sqstm1) in signaling functions central to tumor initiation in the epithelium and suppression of tumor progression in the stroma.
New evidence supports an autophagy-independent key role of the adaptor p62 in cancer.
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.
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•TRAF6 is recruited to mTORC1 through p62 in amino acid-activated cells•TRAF6 is required for mTORC1 activation in response to amino acids•TRAF6-catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids•The TRAF6-p62 complex modulates autophagy and cancer cell proliferation
Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found ...that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.
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•p62 levels are reduced in hepatic stellate cells (HSCs) in human HCC samples•Loss of p62 in HSCs results in increased fibrosis, inflammation, and HCC•p62 is critical for VDR:RXR heterodimerization and inhibition of HSC activation•Enhanced HSC activation by p62 loss impairs VDR signaling and promotes HCC
In hepatocellular carcinoma (HCC), p62 is increased in hepatocytes but decreased in hepatic stellate cells (HSCs). Duran et al. show that loss of p62 in HSCs promotes HCC development by reducing the vitamin D receptor (VDR)-RXR interaction, leading to impaired repression of fibrosis and inflammation by VDR.
Nuclear factor κB (NF-κB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1β and NLRP3 expression. NF-κB, however, also prevents excessive ...inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1β-dependent inflammation, enhancing macrophage death. Therefore, the “NF-κB-p62-mitophagy” pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.
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•NF-κB mediates LPS-induced p62/SQSTM1 expression in macrophages•NLRP3 agonists damage mitochondria and release inflammasome activating signals•Ubiquitinated damaged mitochondria are eliminated by p62-dependent mitophagy•p62 ablation prevents mitophagy and enhances NLRP3-inflammasome activation
NF-κB restrains its own inflammation-promoting activity in macrophages by promoting p62-mediated removal of mitochondria that have been damaged after macrophages encounter various NLRP3-inflammasome activators.
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.
The signaling adaptor p62 is a multidomain protein implicated in the activation of the transcription factor NF-κB. Recent findings link p62 activity to the extrinsic apoptosis pathway, and Mathew et ...al. (2009) now show that the modulation of p62 by autophagy is a key factor in tumorigenesis. These findings place p62 at critical decision points that control cell death and survival.
The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels ...were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.
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•p62 levels are reduced in mouse and human tumor stroma•p62 loss in stromal fibroblasts resulted in increased epithelial tumorigenesis•p62 regulates stromal inflammation by mTor/c-Myc metabolic reprogramming•Stromal metabolic reprogramming is essential for IL-6-driven epithelial tumorigenesis
Valencia et al. show that reduced levels of p62 in cancer-associated fibroblasts increase prostate epithelial cell cancer tumorigenesis. They show that p62 modulates stromal cell glucose and amino acid metabolism through an mTORC1/c-Myc pathway, resulting in increased secretion of tumor-promoting IL-6.
From the very early days of nuclear factor‐κB (NF‐κB) research, it was recognized that different protein kinase C (PKC) isoforms might be involved in the activation of NF‐κB. Pharmacological tools ...and pseudosubstrate inhibitors suggested that these kinases play a role in this important inflammatory and survival pathway; however, it was the analysis of several genetic mouse knockout models that revealed the complexity and interrelations between the different components of the PB1 network in several cellular functions, including T‐cell biology, bone homeostasis, inflammation associated with the metabolic syndrome, and cancer. These studies unveiled, for example, the critical role of PKCζ as a positive regulator of NF‐κB through the regulation of RelA but also its inflammatory suppressor activities through the regulation of the interleukin‐4 signaling cascade. This observation is of relevance in T cells, where p62, PKCζ, PKCλ/ι, and NBR1 establish a mesh of interactions that culminate in the regulation of T‐cell effector responses through the modulation of T‐cell polarity. Many questions remain to be answered, not just from the point of view of the implication for NF‐κB activation but also with regard to the in vivo interplay between these pathways in pathophysiological processes like obesity and cancer.
The signaling adapter p62 plays a coordinating role in mediating phosphorylation and ubiquitin-dependent trafficking of interacting proteins. However, there is little known about the physiologic role ...of this protein in brain. Here, we report age-dependent constitutive activation of glycogen synthase kinase 3β, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62⁻/⁻ mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration. Biochemical fractionation of p62⁻/⁻ brain led to recovery of aggregated K63-ubiquitinated tau. Loss of p62 was manifested by increased anxiety, depression, loss of working memory, and reduced serum brain-derived neurotrophic factor levels. Our findings reveal a novel role for p62 as a chaperone that regulates tau solubility thereby preventing tau aggregation. This study provides a clear demonstration of an Alzheimer-like phenotype in a mouse model in the absence of expression of human genes carrying mutations in amyloid-beta protein precursor, presenilin, or tau. Thus, these findings provide new insight into manifestation of sporadic Alzheimer disease and the impact of obesity.
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