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A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center



* FARE Award Winner


  • Y Liu
  • Q Wang
  • N Soetandyo
  • K Baek
  • R Hegde
  • Y Ye


In eukaryotic cells, Endoplasmic Reticulum-Associated Degradation (ERAD) eliminates misfolded proteins to preserve ER homeostasis. This process requires retrotranslocation of polypeptides in unfolded states by the concerted action of membrane-bound ubiquitin ligases and the translocation-driving ATPase p97. Consequently, polypeptides arriving in the cytosol often bear exposed hydrophobic motifs or transmembrane domain (TMD), which, if not properly shielded, could cause aggregation to prematurely terminate degradation. How retrotranslocated polypeptides avoid aggregation before reaching the proteasome is unclear. Here we identify a ubiquitin ligase-associated multiprotein complex comprising Bag6, Ubl4A, and Trc35, which chaperones retrotranslocated polypeptides en route to the proteasome to improve ERAD efficiency. In vitro, Bag6, the central component of the complex, contains an ATP independent chaperone-like activity capable of maintaining an aggregation-prone substrate in an unfolded yet soluble state. The physiological importance of this holdase activity is underscored by observations that ERAD substrates accumulate in detergent-insoluble aggregates in cells depleted of Bag6, or of Trc35, a cofactor that keeps Bag6 outside the nucleus for engagement in ERAD. Our results reveal a ubiquitin ligase-associated holdase that maintains polypeptide solubility to enhance protein quality control in mammalian cells.

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