Identification of the Roles of the Small Ubiquitin-Related Modifier (SUMO) in Cellular Stress Response
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Date
2015-04-10
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Johns Hopkins University
Abstract
Proper protein folding is essential for cell function, as misfolding leads to cell stress and cytotoxicity. Misfolded proteins are associated with several serious diseases in humans such as Parkinson’s and Alzheimer’s diseases. The posttranslational modifier SUMO has been implicated in several of these diseases, including cystic fibrosis, amyotrophic lateral sclerosis, and other neurodegenerative diseases. However, the mechanism by which SUMO affects protein folding and stress response is not well understood. To address this question, we investigated a SUMO mutant that is sensitive to canavanine, an arginine analog that induces protein misfolding. We characterized this mutant as deficient in binding to proteins containing SUMO-interacting motifs (SIMs) and hypothesized that a high-copy suppressor screen would identify proteins that function downstream of SUMO in the protein stress response. We found that San1, a ubiquitin E3 ligase involved in nuclear protein quality control, can suppress the sensitivity of our mutant to canavanine. Interestingly, the RING domain required for E3 ligase activity is not necessary for suppression, but the unstructured N-terminus of San1 is both necessary and sufficient for suppression. The N-terminus has a chaperone-like function, binding to unstructured, misfolded proteins. Our findings suggest that sumoylation may either play a similar role and promote proper protein folding, or function to prevent the accumulation of toxic misfolded proteins in the cell.
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SUMO, protein folding