Calreticulin Negatively Regulates the Cell Surface Expression of Cystic Fibrosis Transmembrane Conductance Regulator
| Autor: | Tsuyoshi Shuto, Kazutsune Harada, Tsukasa Okiyoneda, Kimitoshi Nakamura, Mary Ann Suico, Yasuaki Hashimoto, Kaori Yamahira, Takuya Sugahara, Keiko Ueno, Ikuo Wada, Hirofumi Kai |
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| Rok vydání: | 2006 |
| Předmět: |
Proteasome Endopeptidase Complex
congenital hereditary and neonatal diseases and abnormalities genetic structures Cell Cystic Fibrosis Transmembrane Conductance Regulator Mice Transgenic CHO Cells Endocytosis Biochemistry Cystic fibrosis Adenoviridae Cell membrane Mice Cricetinae medicine Animals Humans cardiovascular diseases Molecular Biology Gene knockdown biology Endoplasmic reticulum Cell Membrane Cell Biology respiratory system medicine.disease Molecular biology Cystic fibrosis transmembrane conductance regulator respiratory tract diseases Cell biology medicine.anatomical_structure Gene Expression Regulation biology.protein Calreticulin Molecular Chaperones |
| Zdroj: | Journal of Biological Chemistry. 281:12841-12848 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m512975200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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