A Ubiquitin-Dependent Surveillance System Mediates Plasma Membrane Protein Quality Control In Yeast
| dc.contributor.author | Zhao, Yingying | en_US |
| dc.contributor.chair | Roberson, Mark Stephen | en_US |
| dc.contributor.coChair | Emr, Scott David | en_US |
| dc.contributor.committeeMember | Collins, Ruth N. | en_US |
| dc.contributor.committeeMember | Qian, Shu-Bing | en_US |
| dc.date.accessioned | 2013-09-05T15:26:36Z | |
| dc.date.available | 2018-01-29T07:00:32Z | |
| dc.date.issued | 2013-01-28 | en_US |
| dc.description.abstract | A UBIQUITIN-DEPENDENT SURVEILLANCE SYSTEM MEDIATES PLASMA MEMBRANE PROTEIN QUALITY CONTROL IN YEAST Yingying Zhao, Ph. D. Cornell University 2013 A key function of the ubiquitin-proteasome system is targeting of misfolded proteins for degradation. In the cytosol, specialized E3 ligases target soluble misfolded proteins for ubiquitination and subsequent proteasomal degradation. However, the case is more complicated for integral membrane proteins. Following co- translational insertion in the ER membrane, proteins that fail to fold properly in the ER are subject to ER-assisted degradation (ERAD), which involves retrotranslocation of proteins back into the cytosol followed by ubiquitin- dependent proteasomal degradation. Properly folded PM proteins, such as signaling receptors, ion channels, and nutrient transporters, exit the ER and traffic through the Golgi to the cell surface where they mediate their specific functions. Maintenance of proper PM proteostasis, particularly with respect to ion channels and nutrient transporters, is crucial to prevent loss of PM integrity and dissipation of essential ion and chemical gradients. As such, when PM resident proteins become damaged or misfolded, they must be recognized, removed by endocytosis and delivered to the lysosome for degradation. Thus, cells maintain a "cradle to grave" quality monitoring system for integral membrane proteins, yet the mechanisms of iii quality surveillance, particularly at the PM, remain poorly understood. Here we present evidence that the E3 ubiquitin ligase Rsp5, the yeast homolog of Nedd4, is part of a critical protein quality surveillance mechanism at the PM. We show that proteotoxic stress triggers global activation of Rsp5-dependent ubiquitination, endocytosis, and vacuolar trafficking of PM proteins. Mutants defective for this protective response exhibit toxic accumulation of integral membrane proteins at the cell surface and suffer catastrophic loss of PM integrity during misfolding stress, phenotypes that can be suppressed by the presence of chemical chaperones. We present the identification of specific Rsp5 adaptors which target the ubiquitination of misfolded PM proteins during proteotoxic stress. Genetic interaction analysis reveals that this PM quality surveillance mechanism exhibits striking synthetic defects with components of both ERAD and the unfolded protein response, indicating that different quality control pathways cooperate to protect cells during misfolding stress. We propose that this ubiquitin-mediated PM quality surveillance pathway, together with other quality control pathways like ERAD, protects cells from proteotoxic stress by limiting the toxic accumulation of misfolded integral membrane proteins at the PM. iv | en_US |
| dc.identifier.other | bibid: 8267704 | |
| dc.identifier.uri | https://hdl.handle.net/1813/33968 | |
| dc.language.iso | en_US | en_US |
| dc.title | A Ubiquitin-Dependent Surveillance System Mediates Plasma Membrane Protein Quality Control In Yeast | en_US |
| dc.type | dissertation or thesis | en_US |
| thesis.degree.discipline | Physiology | |
| thesis.degree.grantor | Cornell University | en_US |
| thesis.degree.level | Doctor of Philosophy | |
| thesis.degree.name | Ph. D., Physiology |
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