Co-chaperone HSJ1a Dually Regulates the Proteasomal Degradation of Ataxin-3
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Time: 2011-06-07
A histopathological hallmark of many neurodegenerative diseases is that the misfolded proteins form neuronal intracellular inclusions. Many pathological polyglutamine (polyQ) containing inclusions have been found to be co-localized with HSP70 and its co-chaperones, ubiquitin (Ub) and proteasome subunits. Overexpression of HSP70 and its co-chaperone can reduce inclusion formation and suppress the cell death. These findings suggest that molecular chaperones and the Ub-proteasome system (UPS) are contributable to refold or eliminate the misfolded proteins before their aggregation. Combination of these actions plays a central role in the cellular stress response to maintain protein homeostasis in eukaryotes. It is believed that it is the co-chaperones that define the specific function of HSP70. Some multi-domain containing co-chaperones may function in linking the chaperone system and the UPS together.
GAO Xuechao, a student in Dr. HU’s lab, revealed a novel function of the co-chaperone HSJ1a, which contains both the chaperone and ubiquitin binding sites. In this research, they applied exogenous overexpressed ataxin-3 (Atx3), normal with 22 glutamines (Atx322Q) or polyQ expanded (Atx371Q), to mimic the high protein level of Atx3 in cells and to investigate the function of HSJ1a in cell stress response through potential cooperation between HSP70 chaperone and ubiquitination associated degradation. They found that HSJ1a can dually regulate the proteasomal degradation of the cellular overexpressed Atx3 through maintaining a balance between HSP70 binding and Ub binding. Thus, finely modulating the balance of the functions of two HSJ1a domains could be considered as a promising therapeutic strategy for neurodegenerative diseases.
This work entitled “Co-Chaperone HSJ1a Dually Regulates the Proteasomal Degradation of Ataxin-3” was published online in PLoS ONE on May 19th, 2011.
This work was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology, and the National Natural Science Foundation of China. (SIBCB)
AUTHOR CONTACT:
HU Hongyu
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Schematic representation of the proteasomal degradation of Atx3 showing different roles of the two domains of HSJ1a. This model proposes that HSJ1a acts like a balance orchestrating the cellular level of Atx3. The J-domain promotes the proteasomal degradation of Atx3 through HSP70 binding, whereas the UIM domain retards the proteasomal degradation of Atx3 through ubiquitin binding. HSP70 acts as an adaptor to recruit co-chaperones and the substrates. (Diagram provided by Dr. HU Hongyu)
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