Research Article: Huntingtin Interacts with the Cue Domain of gp78 and Inhibits gp78 Binding to Ubiquitin and p97/VCP

Date Published: January 26, 2010

Publisher: Public Library of Science

Author(s): Hui Yang, Chao Liu, Yongwang Zhong, Shouqing Luo, Mervyn J. Monteiro, Shengyun Fang, Neeraj Vij. http://doi.org/10.1371/journal.pone.0008905

Abstract: Huntington’s disease (HD) is caused by polyglutamine expansion in huntingtin (htt) protein, but the exact mechanism of HD pathogenesis remains uncertain. Recent evidence suggests that htt proteins with expanded polyglutamine tracts induce endoplasmic reticulum (ER) stress, probably by interfering with ER-associated degradation (ERAD). Here we report that mutant htt interacts and interferes with the function of gp78, an ER membrane-anchored ubiquitin ligase (E3) involved in ERAD. Mapping studies showed that the HEAT repeats 2&3 of htt interact with the cue domain of gp78. The interaction competitively reduces polyubiquitinated protein binding to gp78 and also sterically blocks gp78 interaction of p97/VCP, a molecular chaperone that is essential for ERAD. These effects of htt negatively regulate the function of gp78 in ERAD and are aggravated by polyglutamine expansion. Paradoxically, gp78 is still able to ubiquitinate and facilitate degradation of htt proteins with expanded polyglutamine. The impairment of ERAD by mutant htt proteins is associated with induction of ER stress. Our studies provide a novel molecular mechanism that supports the involvement of ER stress in HD pathogenesis.

Partial Text: Huntington’s disease (HD) is an inherited neurodegenerative disorder that is caused by abnormal expansion of tri-nucleotide CAG repeats in the first exon of the gene encoding huntingtin (htt) protein [1]–[4]. The expanded CAG repeats are translated into different lengths of polyglutamine tracts: expansions greater than 35 repeats induce HD disease [4], [5], with the age of onset inversely related to the length of the polyglutamine expansion [3], [4].

ER stress is triggered when the production of misfolded proteins in the ER exceeds the capacity of the organelle to refold or dispose the misfolded proteins [46], [60], [61]. The disposal of misfolded proteins from the ER is achieved by ERAD, the main pathway by which misfolded proteins are exported to the cytosol for degradation by proteasomes [62]. In this report we demonstrate that polyglutamine expansions in htt proteins induce ER stress by interfering with the function of gp78, an ER resident E3 that normally functions in ERAD. Our findings suggest that perturbation of gp78 function occurs by three interrelated mechanisms: 1) polyglutamine expansion enhances mutant htt interaction with the cue domain of gp78, thereby severely hindering polyubiquitin binding to the cue domain; 2) mutant htt sterically blocks p97/VCP interaction with gp78; 3) accumulation of mutant htt causes aggregation of gp78. In addition, we showed that gp78 is able to ubiquitinate and enhance mutant htt degradation. This function makes gp78 vulnerable when mutant htt accumulates and aggregates during HD progression.

Source:

http://doi.org/10.1371/journal.pone.0008905

 

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