Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75)

Jennifer L. Kopanic, Barbara Schlingmann, Michael Koval, Alan F. Lau, Paul L Sorgen, Vivian F. Su

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Connexins are a family of transmembrane proteins that form gap junction channels. These proteins undergo both proteasomal and lysosomal degradation, mechanisms that serve to regulate connexin levels. Our previous work described CIP75 [connexin43 (Cx43)-interacting protein of 75 kDa], a protein involved in proteasomal degradation, as a novel Cx43-interacting protein. We have discovered two additional connexins, connexin40 (Cx40) and connexin45 (Cx45), that interact with CIP75. 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 CIP75 by shRNA in HeLa cells expressing Cx40 or Cx45 resulted in increased levels of the connexins. Furthermore, 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. In addition, we have also discovered that CIP75 interacts with ER-localized Cx32 in a process that is likely mediated by Cx32 ubiquitination. Thus, we have identified novel interacting connexin proteins of CIP75, indicating a role for CIP75 in regulating the levels of connexins in general, through proteasomal degradation.

Original languageEnglish (US)
Pages (from-to)571-585
Number of pages15
JournalBiochemical Journal
Volume466
Issue number3
DOIs
StatePublished - Mar 15 2015

Fingerprint

Connexin 43
Connexins
Gap Junctions
Degradation
Proteins
Endoplasmic Reticulum-Associated Degradation
Ubiquitination
HeLa Cells
Small Interfering RNA

Keywords

  • CIP75
  • Connexin
  • ERAD
  • Proteasome
  • Protein degradation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75). / Kopanic, Jennifer L.; Schlingmann, Barbara; Koval, Michael; Lau, Alan F.; Sorgen, Paul L; Su, Vivian F.

In: Biochemical Journal, Vol. 466, No. 3, 15.03.2015, p. 571-585.

Research output: Contribution to journalArticle

Kopanic, Jennifer L. ; Schlingmann, Barbara ; Koval, Michael ; Lau, Alan F. ; Sorgen, Paul L ; Su, Vivian F. / Degradation of gap junction connexins is regulated by the interaction with Cx43-interacting protein of 75 kDa (CIP75). In: Biochemical Journal. 2015 ; Vol. 466, No. 3. pp. 571-585.
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