title: Importin beta interacts with the endoplasmic reticulum-associated degradation machinery and promotes ubiquitination and degradation of mutant alpha1-antitrypsin.
abstract: The mechanism by which misfolded proteins in the endoplasmic reticulum (ER) are retrotranslocated to the cytosol for proteasomal degradation is still poorly understood. Here, we show that importin β, a well established nucleocytoplasmic transport protein, interacts with components of the retrotranslocation complex and promotes ER-associated degradation (ERAD). Knockdown of importin β specifically inhibited the degradation of misfolded ERAD substrates but did not affect turnover of non-ERAD proteasome substrates. Genetic studies and in vitro reconstitution assays demonstrate that importin β is critically required for ubiquitination of mutant α1-antitrypsin, a luminal ERAD substrate. Furthermore, we show that importin β cooperates with Ran GTPase to promote ubiquitination and proteasomal degradation of mutant α1-antitrypsin. These results establish an unanticipated role for importin β in ER protein quality control.
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, Maryland 21201, USA.
authors.forename: Yongwang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Petek
authors.initials: P
authors.lastname: Ballar
authors.forename: Jin-gu
authors.initials: JG
authors.lastname: Lee
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.forename: Mervyn J
authors.initials: MJ
authors.lastname: Monteiro
authors.forename: Shengyun
authors.initials: S
authors.lastname: Fang
mesh_terms: D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C120587:RAN protein, human; D000515:alpha 1-Antitrypsin; D028961:beta Karyopherins; D046988:Proteasome Endopeptidase Complex; D020931:ran GTP-Binding Protein