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J. Biol. Chem., Vol. 283, Issue 9, 5748-5759, February 29, 2008

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A Novel Connexin43-interacting Protein, CIP75, Which Belongs to the UbL-UBA Protein Family, Regulates the Turnover of Connexin43^*

Xinli Li¹, Vivian Su¹, Wendy E. Kurata, Chengshi Jin, and Alan F. Lau^¶2

From the Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, Honolulu, Hawaii 96813, the Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California 94143, and the ^¶Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii 96822

The degradation of connexin43 (Cx43) has been reported to involve both lysosomal and proteasomal degradation pathways; however, very little is known about the mechanisms regulating these Cx43 degradation pathways. Using yeast two-hybrid, glutathione S-transferase pull-down, and co-immunoprecipitation approaches, we have identified a novel Cx43-interacting protein of 75 kDa, CIP75. Laser confocal microscopy showed that CIP75 is located primarily at the endoplasmic reticulum, as indicated by the calnexin marker, with Cx43 co-localization in this perinuclear region. CIP75 belongs to the UbL (ubiquitin-like)-UBA (ubiquitin-associated) domain-containing protein family with a N-terminal UbL domain and a C-terminal UBA domain. The UBA domain of CIP75 is the main element mediating the interaction with Cx43, whereas the CIP75-interacting region in Cx43 resides in the PY motif and multiphosphorylation sites located between Lys²⁶⁴ and Asn³⁰². Interestingly, the UbL domain interacts with the S2/RPN1 and S5a/RPN10 protein subunits of the regulatory 19 S proteasome cap subunit of the 26 S proteasome complex. Overexpression experiments suggested that CIP75 is involved in the turnover of Cx43 as measured by a significant stimulation of Cx43 degradation and reduction in its half-life with the opposite effects on Cx43 degradation observed in small interference RNA knockdown experiments.

Received for publication, November 12, 2007 , and in revised form, December 12, 2007.

^* This work was supported by Grant CA052098 from the National Institutes of Health (to A. F. L.), and predoctoral fellowship HIFW-29-96 (to C. J.) from the American Heart Association, Hawaii Affiliate. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Natural Products and Cancer Biology Program, Cancer Research Center of Hawaii, 651 Ilalo St., BSB 222L, Honolulu, HI 96813. Tel.: 808-586-2959; Fax: 808-587-0742; E-mail: aflau{at}crch.hawaii.edu.

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