Authors:
Amirthaa Suntharalingam, Jose F. Abisambra, John C. O'Leary III, John Koren III, Bo Zhang, Myung Kuk Joe, Laura J. Blair, Shannon E. Hill, Umesh K. Jinwal, Matthew Cockman, Adam S. Duerfeldt, Stanislav Tomarev, Brian S.J. Blagg, Raquel L. Lieberman, and Chad A. Dickey
Summary:
Clearance of misfolded proteins in the endoplasmic reticulum (ER) is traditionally handled by ER-associated degradation, a process that requires retro-translocation and ubiquitination mediated by a lumenal chaperone network. Here we investigated whether the secreted, glaucoma-associated protein myocilin was processed by this pathway. Myocilin is typically transported through the ER/Golgi network, but inherited mutations in myocilin lead to its misfolding and aggregation within trabecular meshwork cells, and ultimately, ER-stress induced cell death. Using targeted knockdown strategies, we determined that Grp94, the ER equivalent of Hsp90, specifically recognizes mutant myocilin, triaging it through ERAD. The addition of mutant myocilin to the short list of Grp94 clients strengthens the hypothesis that beta-strand secondary structure drives client association with Grp94. Interestingly, the ERAD pathway is incapable of efficiently handling the removal of mutant myocilin, but when Grp94 is depleted, degradation of mutant myocilin is shunted away from ERAD towards a more robust clearance pathway for aggregation-prone proteins, the autophagy system. Thus ERAD inefficiency for distinct aggregation-prone proteins can be subverted by manipulating ER chaperones, leading to more effective clearance by the autophagic/lysosomal pathway. General Hsp90 inhibitors and a selective Grp94 inhibitor also facilitate clearance of mutant myocilin, suggesting that therapeutic approaches aimed at inhibiting Grp94 could be beneficial for patients suffering from some cases of myocilin glaucoma.
Source:
The Journal of Biological Chemistry; (10/03/12)