Gromeier, MatthiasKastan, Jonathan2021-01-122023-01-112020https://hdl.handle.net/10161/22137<p>In the following document, I will describe two distinct strategies that poliovirus</p><p>(PV) deploys to manage host antiviral responses. In the first section, I report on a role of</p><p>the constitutive repressor of eIF2α phosphorylation (CReP) in translation of PV and the</p><p>endoplasmic reticulum (ER)-resident chaperone binding immunoglobulin protein (BiP)</p><p>at the ER. Functional, proximity-dependent labeling and cell fractionation studies</p><p>revealed that CReP, through binding of the eukaryotic translation initiation factor eIF2α,</p><p>anchors translation initiation machinery at the ER and enables protein synthesis in this</p><p>compartment. This ER site was protected from the suppression of cytoplasmic protein</p><p>synthesis by acute stress responses. I propose that partitioning of translation initiation</p><p>machinery at the ER enables cells to maintain active translation of PV during stress.</p><p>In the second section, I report that PV 2A protease cleaves all three members of</p><p>the YTHDF protein family, cytosolic N6-methyladenosine (m6A) ‘readers’ that regulate</p><p>target mRNA fate. These cleavages occurred early during infection, and preemptive</p><p>YTHDF3 depletion enhanced viral replication. This corresponded with diminished type-</p><p>I interferon (IFN) receptor (IFNAR) expression and IFN-stimulated gene induction,</p><p>while IFN production was not significantly changed. I propose that 2A protease cleaves</p><p>YTHDF proteins, in part, to interfere with IFNAR expression and antagonize the host</p><p>antiviral response.</p>VirologyeIF2ERMethylationPoliovirusStressTranslationDissertation