8.A.52 The Ubiquitin-related Protein Degradation (UPD) Family 

Connexins, gap junction channels (TC# 1.A.24), undergo both proteasomal and lysosomal degradation, regulating connexin levels. CIP75 [connexin43 (Cx43; TC# 1.A.24.1.1)-interacting protein of 75 kDa], a protein involved in proteasomal degradation, interacts with several connexins. These include connexin40 (Cx40; TC#1.A.24.1.8) and connexin45 (Cx45; TC#1.A.24.2.4). Nuclear magnetic resonance (NMR) analyses identified the direct interaction of the CIP75 UBA domain with the carboxyl-terminal (CT) domains of Cx40 and Cx45. Reduction in the concentration of CIP75 resulted in increased levels of the connexins, and treatment with trafficking inhibitors confirmed that both connexins undergo endoplasmic reticulum-associated degradation (ERAD), and that CIP75 preferentially interacts with the connexin proteins bound for proteasomal degradation from the ER. CIP75 also interacts with ER-localized Cx32 (TC# 1.A.24.1.3) in a process that is likely mediated by Cx32 ubiquitination. Thus, CIP75 regulates the levels of connexins through proteasomal degradation.  The prototype member of this family, CIP75, has a region of homology with Ubiquitin extension protein 4 (TC#3.A.25.1.1; B7FZS1) and Polyubiquitin (TC# 3.A.16.1.3; Q7KQK2).