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Cellular function depends critically on not only appropriate expression of the correct proteins, but also on their precise localization within the cell. Identifying and getting rid of improperly localized copies of a protein represent constant housekeeping tasks for any cell. How is this accomplished? To address this question, we are asking what happens to the population of secretory and membrane proteins that fail to be segregated into the ER (see Figure). While the simple answer to this question is that they are degraded, a more precise answer delineating the pathway of their selective recognition, ubiquitination, and degradation is lacking. Because these proteins are often quite hydrophobic and/or contain unprocessed hydrophobic elements, they represent a high risk for aggregation and inappropriate interactions. Thus, the pathway for the selective recognition and degradation of non-translocated secretory and membrane proteins is likely to be of importance not only during ER stress (when translocation of many proteins is attenuated), but also for normal cellular homeostasis. We are investigating this issue using both classical fractionation and affinity purification approaches to identify the machinery for the selective recognition and degradation of these non-translocated proteins.
