Exploring accessible nodes in the Unfolded Protein Response (360G-Wellcome-200848_Z_16_Z)

Protein folding homeostasis (proteostasis) in the endoplasmic reticulum (ER) intercedes in biological processes with consequences to diseases of aging. Cells cope with ER stress by addressing features common to most unfolded (and misfolded) proteins. Implementing the apparatus for this Unfolded Protein Response (UPR) entails tradeoffs that affect fitness in circumstance-dependent ways. Our research program is predicated on the notion that a detailed understanding of the UPR will identify failures of homeostasis that may be exploited therapeutically. We shall focus on four promising and underexplored nodes. The first two emerge from study of the signaling pathway by which cells downregulate global protein synthesis in response to ER stress, which hinges on phosphorylated translation initiation factor, eIF2a. We seek a detailed biochemical and structural understanding of eIF2alphaP dephosphorylation by PPP1R15-containing holophosphatases (whose inhibition promotes resistance to ER stress) and the action of eIF2B, a guanine nucleotide exchange factor [the target of eIF2(alphaP)]. Nodes 3 and 4 concern the machinery that regulates proteostasis by inactivating the ER chaperone BiP through enforced oligomerization or covalent modification. Delineating the UPR’s fundamentals is the foundation for the rapidly-advancing research into the experimental pathology of ER stress and fuels this important translational effort.