Sequestosome 1 (SQSTM1) (SQSTM1)

Sequestosome 1 (SQSTM1), commonly referred to as p62, is a multifunctional scaffold protein that plays a critical role in selective autophagy and cellular signaling (UniProt P35354). It functions as an autophagy adapter by bridging polyubiquitinated protein aggregates to the autophagosome through its C-terminal ubiquitin-associated (UBA) domain and its LC3-interacting region (LIR) (PubMed: 27050110). Beyond its role in degradation, p62 serves as a signaling hub for the NF-κB, mTORC1, and Nrf2 pathways, thereby regulating cell survival, growth, and the oxidative stress response (PubMed: 26515531). Mutations in SQSTM1 are strongly linked to Paget's disease of bone and neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (NIH Gene ID: 8878). In oncology, p62 often accumulates in tumor cells due to impaired autophagy, where it promotes pro-survival signaling and therapeutic resistance. Current drug discovery efforts target p62's specific domains, such as the ZZ domain or the Keap1-interacting region, to inhibit its pathological functions in cancer and inflammatory diseases.

Other names

p62Ubiquitin-binding protein p62EBI3-associated protein of 60 kDaPhosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDaA170OSILZIPZIP3DMRV

Inhibition of the ZZ domain to block pro-survival signaling pathways or disruption of the p62-Keap1 interaction to modulate the Nrf2-mediated antioxidant response.