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MBC in Press, published online ahead of print January 23, 2008
Mol. Biol. Cell 10.1091/mbc.E07-06-0601

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Submitted on June 25, 2007
Revised on January 4, 2008
Accepted on January 16, 2008

Gp78 Cooperates with RMA1 in ER-associated Degradation of CFTR{Delta}F508

Daisuke Morito,* Kazuyoshi Hirao,* Yukako Oda,{dagger} Nobuko Hosokawa,* Fuminori Tokunaga,{ddagger} Douglas M. Cyr,{sect} Keiji Tanaka,|| Kazuhiro Iwai,{dagger} and Kazuhiro Nagata*

* Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan, Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Japan; {dagger}Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan; {ddagger}Department of Molecular Cell Biology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan; {sect}Department of Cell and Developmental Biology, UNC Cystic Fibrosis Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599; ||Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan

Monitoring Editor: Thomas Sommer

Misfolded or improperly assembled proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded via the ubiquitin-proteasome pathway, a process termed ER-associated degradation (ERAD). S. cerevisiae Hrd1p/Der3p is an ER membrane-spanning ubiquitin ligase that participates in ERAD of the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is exogenously expressed in yeast cells. Two mammalian orthologues of yeast Hrd1p/Der3p, gp78 and HRD1, have been reported. Here we demonstrate that gp78, but not HRD1, participates in ERAD of the CFTR mutant CFTR{Delta}F508, by specifically promoting ubiquitylation of CFTR{Delta}F508. Domain swapping experiments and deletion analysis revealed that gp78 binds to CFTR{Delta}F508 through its ubiquitin binding region, the so-called CUE (coupling of ubiquitin to ER degradation) domain. Gp78 poly-ubiquitylated in vitro an N-terminal ubiquitin-glutathione-S-transferase (GST) fusion protein, but not GST alone. This suggests that gp78 recognizes the ubiquitin that is already conjugated to CFTR{Delta}F508 and catalyzes further poly-ubiquitylation of CFTR{Delta}F508 in a manner similar to that of a multi-ubiquitin chain assembly factor (E4). Furthermore, we revealed by siRNA methods that the ubiquitin ligase RMA1 functioned as an E3 enzyme upstream of gp78. Our data demonstrates that gp78 cooperates with RMA1 with E4-like activity in the ERAD of CFTR{Delta}F508.

Address correspondence to: Kazuhiro Nagata (nagata{at}frontier.kyoto-u.ac.jp)




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