Chemical‐genetic activation of the Unfolded Protein Response reduces protein misfolding

Abstract

Unfolded Protein Response (UPR) comprises a set of intracellular signaling pathways ‐ controlled by Ire1, Perk, and Atf6 genes ‐ that detect protein misfolding in the endoplasmic reticulum (ER) and activate a broad transcriptional program that restores cellular proteostasis. UPR transcriptional targets include chaperones, ER‐associated protein degradation (ERAD) and the ubiquitin‐proteasome system components, and ER structural and transport proteins. Many human diseases arise from protein misfolding. We hypothesized that UPR signaling could be harnessed to prevent protein misfolding. To test this, we developed chemical‐genetic tools that allowed us to selectively activate individual UPR pathways. We then assessed how individual UPR pathways affected rhodopsin protein bearing a proline to histidine missense mutation at residue 23 (P23H). P23H rhodopsin was previously demonstrated to form insoluble aggregates that are retained in the ER and ultimately cause cell death and hereditary Retinitis Pigmentosa. We found that artificial UPR signaling selectively removed misfolded rhodopsin from the ER and enhanced its degradation. This suggests that UPR signaling pathways may be used to treat protein misfolding diseases.(Supported by NIH EY018313, Fight for Sight Foundation, Cystic Fibrosis Foundation, and American Federation for Aging Research)