Calreticulin negatively regulates the cell surface expression of cystic fibrosis transmembrane conductance regulator.
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.
Harada
Kazutsune
K
Department of Molecular Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Okiyoneda
Tsukasa
T
Hashimoto
Yasuaki
Y
Ueno
Keiko
K
Nakamura
Kimitoshi
K
Yamahira
Kaori
K
Sugahara
Takuya
T
Shuto
Tsuyoshi
T
Wada
Ikuo
I
Suico
Mary Ann
MA
Kai
Hirofumi
H
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D037282:Calreticulin / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000502:physiology*; D004705:Endocytosis; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D037282:Calreticulin; D018832:Molecular Chaperones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D046988:Proteasome Endopeptidase Complex