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 ?, a well established nucleocytoplasmic transport protein, interacts with components of the retrotranslocation complex and promotes ER-associated degradation (ERAD). Knockdown of importin ? 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 ? is critically required for ubiquitination of mutant ?1-antitrypsin, a luminal ERAD substrate. Furthermore, we show that importin ? cooperates with Ran GTPase to promote ubiquitination and proteasomal degradation of mutant ?1-antitrypsin. These results establish an unanticipated role for importin ? in ER protein quality control.

SUBMITTER: Zhong Y 

PROVIDER: S-EPMC3190800 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other