A novel pathway to clear cells of misfolded proteins

Division Of Basic Sciences - Nci

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Abstract

We have identified a novel pathway for clearing misfolded cytosolic proteins from human cells that directs them to the endoplasmic reticulum (ER). This pathway is used to clear cells of a naturally occurring misfolded NAT1 variant; NAT enzymes acetylate arylamines leading to their detoxification. NAT1 WT by contrast is stable and not present at the ER. We have found other candidates in the literature that may be degraded in this manner and are testing this model further. We are also performing experiments to identify the components involved in this quality control pathway. Importantly, we are looking into exploiting this pathway as a method for clearing cells of misfolded or damaged constituents that persist in human cells and are associated with human diseases. Parkin R42P is an example of a naturally occurring misfolded protein that is trafficked poorly to ER and stable. This Parkin variant is associated with Juvenille Parkinsonism and has a mutation in its N-terminal UBL domain that renders it unstructured. We also find that we can artificially direct Parkin R42P to ER by fusion with the Sec61beta ER-directing transmembrane domain and that this induced ER-localization triggers its clearance. We are expanding on these findings to test further the application of routing misfolded cytosolic proteins to the ER as a strategy for clearance.