| Phospho‑SQSTM1/p62 (Ser349) denotes the active, signal-integrating form of the autophagy adaptor SQSTM1/p62 in which a serine residue within the KEAP1-binding region is phosphorylated, enhancing the protein’s ability to couple selective autophagy with redox-responsive transcriptional control. SQSTM1/p62 is a modular scaffold with an N‑terminal PB1 domain that mediates self-oligomerization, central LC3-interacting and KEAP1-interacting regions, and a C‑terminal ubiquitin-associated domain, allowing it to assemble phase‑separated droplets that concentrate polyubiquitinated cargo, autophagy machinery, and signaling components. Phosphorylation at Ser349 (Ser351 in mouse) occurs within the KEAP1-interacting region and increases the affinity of p62 for KEAP1, promoting competitive binding that displaces NRF2 from the KEAP1–CUL3 ubiquitin ligase complex and stabilizes NRF2, which then accumulates in the nucleus and activates transcription of antioxidant and cytoprotective genes. This modification is induced during oxidative stress and integrates with additional phosphorylation events such as Ser403, which strengthens binding to polyubiquitin chains, so that Ser349‑phosphorylated p62 droplets function as platforms where ubiquitinated cargo, KEAP1, and autophagy factors converge, coordinating NRF2 activation with cargo sequestration and autophagic degradation. Phospho‑p62 (Ser349) thereby marks a state in which p62 not only serves as a receptor for selective autophagy of ubiquitinated proteins, protein aggregates, and damaged organelles, but also actively rewires the KEAP1–NRF2 axis toward an antioxidant and pro-survival transcriptional program, a coupling that contributes to adaptation under chronic stress. In cancer, persistent or elevated Ser349 phosphorylation associates with increased NRF2 activity, resistance to anticancer drugs, and enhanced proliferative capacity of hepatocellular carcinoma and other tumor cells, and phospho‑Ser349 p62 is enriched in p62-positive inclusion bodies where it supports both survival signaling and altered proteostasis, making this epitope a useful readout of NRF2‑linked autophagy signaling in oncogenic contexts. |
