HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 18, 12841-12848, May 5, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/18/12841    most recent M512975200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harada, K. Articles by Kai, H. Search for Related Content PubMed PubMed Citation Articles by Harada, K. Articles by Kai, H. Social Bookmarking                      What's this?

Calreticulin Negatively Regulates the Cell Surface Expression of Cystic Fibrosis Transmembrane Conductance Regulator^*

Kazutsune Harada¹, Tsukasa Okiyoneda¹, Yasuaki Hashimoto, Keiko Ueno, Kimitoshi Nakamura, Kaori Yamahira, Takuya Sugahara, Tsuyoshi Shuto, Ikuo Wada^¶, Mary Ann Suico, and Hirofumi Kai²

From the Departments of Molecular Medicine and Pediatrics, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan and the ^¶Department of Cell Science, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan

Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent Cl^- channel at the plasma membrane, and its malfunction results in cystic fibrosis, the most common lethal genetic disease in Caucasians. Quality control of CFTR is strictly regulated by several molecular chaperones. Here we show that calreticulin (CRT), which is a lectin-like chaperone in the endoplasmic reticulum (ER), negatively regulates the cell surface CFTR. RNA interference-based CRT knockdown induced the increase of CFTR expression. Consistently, this effect was observed in vivo. CRT heterozygous (CRT^+/-) mice had a higher endogenous expression of CFTR than the wild-type mice. Moreover, CRT overexpression induced cell surface expression of CRT, and it significantly decreased the cell surface expression and function of CFTR. CRT overexpression destabilized the cell surface CFTR by enhancing endocytosis, leading to proteasomal degradation. Deletion of the carboxyl domain of CRT, which results in its ER export, increased the negative effect and enhanced the interaction with CFTR. Thus, CRT in the post-ER compartments may act as a negative regulator of the cell surface CFTR.

Received for publication, December 5, 2005 , and in revised form, February 24, 2006.

^* This work was supported by grants from the Ministry of Education, Science, Sport, and Culture of Japan and by a Sasakawa scientific research grant from The Japan Science Society. 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 material.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-96-371-4405; Fax: 81-96-371-4405; E-mail: hirokai{at}gpo.kumamoto-u.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Glozman, T. Okiyoneda, C. M. Mulvihill, J. M. Rini, H. Barriere, and G. L. Lukacs N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic J. Cell Biol., March 23, 2009; 184(6): 847 - 862. [Abstract] [Full Text] [PDF]

				T. W. Loo, M. C. Bartlett, and D. M. Clarke Insertion of an Arginine Residue into the Transmembrane Segments Corrects Protein Misfolding J. Biol. Chem., October 6, 2006; 281(40): 29436 - 29440. [Abstract] [Full Text] [PDF]