Sequestosome 1 (p62) (SQSTM1)

Sequestosome 1 (p62/SQSTM1) is a multifunctional scaffold protein that serves as a critical link between the autophagy machinery and various cell signaling pathways (UniProt P35906). It contains a ZZ-type zinc finger domain that mediates a specific protein-protein interaction with Receptor-Interacting Protein 1 (RIP1), which is essential for the activation of the NF-kappaB signaling pathway (PubMed: 10747021). This interaction plays a significant role in regulating inflammation, cell survival, and bone remodeling, and its dysregulation is a hallmark of Paget's disease of bone and certain cancers like multiple myeloma (PubMed: 24121501). Therapeutic targeting of the p62 ZZ domain aims to disrupt the p62-RIP1 interface to inhibit aberrant NF-kappaB signaling without affecting other p62 functions like autophagy (PubMed: 25611386). Small molecule inhibitors, such as XRK3, have been developed to specifically bind the ZZ domain and have shown promise in preclinical models for treating bone-related disorders and hematological malignancies (PubMed: 25611386). By selectively blocking this interface, these drugs offer a targeted approach to managing diseases driven by p62-mediated signaling dysfunction.

Other names

p62EBI3-associated protein of 60 kDaEBIAPUbiquitin-binding protein p62Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDaZIP3OSIL

Inhibition of the protein-protein interaction between the p62 ZZ domain and RIP1 to modulate NF-kappaB signaling and autophagy.