Importin beta Interacts with the Endoplasmic Reticulum-associated Degradation Machinery and Promotes Ubiquitination and Degradation of Mutant alpha 1-Antitrypsin


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ZHONG Y., WANG Y., YANG H., Ballar P. , LEE J., YE Y., ...Daha Fazla

JOURNAL OF BIOLOGICAL CHEMISTRY, cilt.286, ss.33921-33930, 2011 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 286 Konu: 39
  • Basım Tarihi: 2011
  • Doi Numarası: 10.1074/jbc.m111.272906
  • Dergi Adı: JOURNAL OF BIOLOGICAL CHEMISTRY
  • Sayfa Sayıları: ss.33921-33930

Özet

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