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Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle
Title: | Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle |
Authors: | Ito, Daisuke Browse this author | Koshino, Ichiro Browse this author | Arashiki, Nobuto Browse this author | Adachi, Hirokazu Browse this author | Tomihari, Mizuki Browse this author | Tamahara, Satoshi Browse this author | Kurogi, Kazuhito Browse this author | Amano, Takashi Browse this author | Ono, Ken-ichiro Browse this author | Inaba, Mutsumi Browse this author →KAKEN DB |
Keywords: | ER-associated degradation (ERAD) | Proteasome | Ubiquitylation | AE1 | Dominant negative | Hereditary spherocytosis |
Issue Date: | 1-Sep-2006 |
Publisher: | The Company of Biologists Ltd |
Journal Title: | Journal of Cell Science |
Volume: | 119 |
Issue: | 17 |
Start Page: | 3602 |
End Page: | 3612 |
Publisher DOI: | 10.1242/jcs.03101 |
PMID: | 16912075 |
Abstract: | Various mutations in the AE1 (anion exchanger 1, band 3) gene cause dominant hereditary spherocytosis, a common congenital hemolytic anemia associated with deficiencies of AE1 of different degrees and loss of mutant protein from red blood cell membranes. To determine the mechanisms underlying decreases in AE1 protein levels, we employed K562 and HEK293 cell lines and Xenopus oocytes together with bovine wild-type AE1 and an R664X nonsense mutant responsible for dominant hereditary spherocytosis to analyze protein expression, turnover, and intracellular localization. R664X-mutant protein underwent rapid degradation and caused specifically increased turnover and impaired trafficking to the plasma membrane of the wild-type protein through hetero-oligomer formation in K562 cells. Consistent with those observations, co-expression of mutant and wild-type AE1 reduced anion transport by the wild-type protein in oocytes. Transfection studies in K562 and HEK293 cells revealed that the major pathway mediating degradation of both R664X and wild-type AE1 employed endoplasmic reticulum (ER)-associated degradation through the proteasomal pathway. Proteasomal degradation of R664X protein appeared to be independent of both ubiquitylation and N-glycosylation, and aggresome formation was not observed following proteasome inhibition. These findings indicate that AE1 R664X protein, which is associated with dominant hereditary spherocytosis, has a dominant-negative effect on the expression of wild-type AE1. |
Rights: | Reproduced with permission of the Company of Biologists. |
Type: | article (author version) |
URI: | http://hdl.handle.net/2115/14879 |
Appears in Collections: | 獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 稲葉 睦
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