Study Of Interaction Between Connexin31and P62

Gap junctions are assembled by a family of transmembrane proteins named connexins. They facilitate direct communication of neighbouring cells via mediating small molecule exchange. Connexin31(Cx31) is a β genusa connexin. Mutations in Cx31are associated with skin diseases, hearing loss and peripheral neuropathy. Connexins are degraded by both lysosomal or proteasomal pathways. Sequestosome-1(SQSTM1)/p62is a scaffold protein containing multiple domains including PB1domain, LIR domain and UBA domain. The PB1domain enables p62to interact with proteins contained PB1domain. p62binds directly to LC3via the LIR motif. The UBA domain of p62interacts with both mono-and poly-ubiquitin. p62is involved in a variety of physiological and pathological processes, including selective autophagy, lipid metabolism, insulin resistance and tumorigenesis. In the present study, we have found that Cx31interacts with p62. p62is colocalized with Cx31at gap junctions as well as cytoplasm. Further studies reveal that p62harboring PB1dysfunction mutant disrupts colocalization with Cx31at gap junctions, but has no effect on Cx31-p62interaction. In contrast, p62UBA and LIR domain dysfunction mutants show little effect on either p62gap junction localization or p62-Cx31intereaction. Knockdown of p62expression reduces Cx31degradation mediated by both proteasomal and lysosomal pathways, increases cell surface presentation of Cx31, and increases colocalization of Cx31and late endosome marker Lampl. Together, the results suggest that p62regulates Cx31metabolism likely via facilitating degradation and recycling of Cx31gap junctions. These findings provide a novel molecule mechanism of Cx31metabolism.