Abstract
Autophagy and the Keap1–Nrf2 system are major cellular defense mechanisms against metabolic and oxidative stress. These two systems are linked via phosphorylation of the ubiquitin binding autophagy receptor protein p62/SQSTM1 in the p62–Keap1–Nrf2 pathway. The p62–Keap1–Nrf2 pathway plays a protective role in normal cells; however, recent studies indicate that this pathway induces tumorigenesis of pre-malignant cells, and promotes the growth and drug resistance of tumor cells via metabolic reprogramming mediated by Nrf2 activation. These findings suggest that impairment of autophagy is involved in the acquisition of malignancy and maintenance of tumors, and furthermore, that p62/SQSTM1 could be a potential target for chemotherapy in cancers that harbor excess p62.
Highlights
Autophagy is a bulk degradation process in which cytoplasmic components are sequestered in a double-membrane structure to form an autophagosome
We demonstrated that phosphorylation of p62 at serine 349 results in nuclear factor erythroid 2-related factor 2 (Nrf2) activation [6]. p62 has a Keap1-interacting region (KIR) motif (349-STGE-352) [36], which allows binding to Keap1DC, but its affinity to Keap1 is significantly lower compared to the ETGE motif of Nrf2
Recent studies demonstrate that Nrf2 increases the expression of multiple enzymes involved in the pentose phosphate pathway, purine nucleotide synthesis, as well as glutathione synthesis, and glutaminolysis in lung cancer, which activates the phosphatidylinositol 3-kinase-Akt pathway [61]. In support of these findings, we found that Nrf2 activation provided metabolic reprogramming of glucose and glutamine through the activation of Nrf2 in hepatocellular carcinoma (HCC) harboring phosphorylated p62 (p-S349) (Figure 3B), which led to increased cell proliferation and resistance to anti-cancer agents of HCC [37] (Figure 4)
Summary
Autophagy is a bulk degradation process in which cytoplasmic components are sequestered in a double-membrane structure to form an autophagosome. On the other hand, removes specific substrates, including protein aggregates, damaged organelles, and invading bacteria This selective pathway uses autophagic receptor proteins for efficient degradation. Ubiquitin binding receptors include p62/SQSTM1, neighbor of BRCA1 gene (NBR1), optineurin, nuclear dot protein 52 kDa/calcium binding and coiled-coil domain (CALCOCO2), Tax binding protein 1, and toll-interacting protein; membrane binding receptors include BCL2/adenovirus E1B 19 kDa interacting protein 3-like (NIX/BNIP3L), BNIP3, FUN14 domain containing 1, and family with sequence similarity 134, member B (FAM134B) [2] These receptors recognize and sort substrates, and recruit core autophagic machinery to the target at existing autophagosome formation sites. The aforementioned diseases are thought to result from loss or dysfunction of p62-regulated cell signaling
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