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Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle

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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)

Submitter: 稲葉 睦

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