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).
References:
Du, Q., X. Wu, K. Ma, W. Liu, P. Liu, T. Hayashi, K. Mizuno, S. Hattori, H. Fujisaki, and T. Ikejima. (2023). Silibinin alleviates ferroptosis of rat islet β cell INS-1 induced by the treatment with palmitic acid and high glucose through enhancing PINK1/parkin-mediated mitophagy. Arch Biochem Biophys 109644. [Epub: Ahead of Print]
Grimaldo, L., A. Sandoval, P. Duran, L. Gómez Flores-Ramos, and R. Felix. (2022). The ubiquitin E3 ligase Parkin regulates neuronal Ca1.3 channel functional expression. J Neurophysiol 128: 1555-1564.
Kopanic, J.L., B. Schlingmann, M. Koval, A.F. Lau, P.L. Sorgen, and V.F. Su. (2015). Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75). Biochem. J. 466: 571-585.
Examples:
TC#	Name	Organismal Type	Example
8.A.52.1.1	*Connexin-interacting protein of 75 KDa (CIP75) or Ubiquitin-4 (UBIN4; UBQLN4; C1 orf6) of 601 aas (Kopanic et al.* 2015).**	Animals	CIP75 of Homo sapiens

8.A.52.1.2	Ubiquitin-1-like isoform X2 of 523 aas	Animals	*Ubiquitin-like isoform X2 of Bombyx mori* (Silk moth)**

8.A.52.1.3	Ubiquitin-like protein of 306 aas	Fungi	Ubiquitin-like protein of Sclerotinia sclerotiorum (White mold) (Whetzelinia sclerotiorum)

8.A.52.1.4	Ubiquitin-like protein of 317 aas	Euglenozoa	Ubiquitin-like protein of Leishmania mexicana

8.A.52.1.5	Deubiquitinylation-prevention protein, Dph1, of 431 aas	Fungi	Dph1 of Neurospora crassa

8.A.52.1.6	Ubiquitin-like protein of 386 aas	Fungi	Ubiquitin-like protein of Glarea lozoyensis

8.A.52.1.7	Ubiquitin of 197 aas	Algae	*Ubiquitin of Griffithsia japonica* (Red alga)**

Examples:
TC#	Name	Organismal Type	Example
8.A.52.2.1	E3 ubiquitin-protein ligase, parkin (PRKN), of 465 aas and 0 - 1 TMSs. Parkin regulates neuronal Ca_V1.3 channel functional expression (Grimaldo et al. 2022). It is a target of mutations in parkinson's disease. Silibinin alleviates ferroptosis of rat islet β cell INS-1 induced by treatment with palmitic acid and high glucose through enhancing PINK1/parkin-mediated mitophagy (Du et al. 2023).		Parkin of Homo sapiens