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dc.contributor.authorYoon, Jimin
dc.contributor.authorNekongo, Emmanuel E
dc.contributor.authorPatrick, Jessica E
dc.contributor.authorHui, Tiffani
dc.contributor.authorPhillips, Angela M
dc.contributor.authorPonomarenko, Anna I
dc.contributor.authorHendel, Samuel J
dc.contributor.authorSebastian, Rebecca M
dc.contributor.authorZhang, Yu Meng
dc.contributor.authorButty, Vincent L
dc.contributor.authorOgbunugafor, C Brandon
dc.contributor.authorLin, Yu-Shan
dc.contributor.authorShoulders, Matthew D
dc.date.accessioned2022-03-18T18:58:36Z
dc.date.available2022-03-18T18:58:36Z
dc.date.issued2022-02-18
dc.identifier.urihttps://hdl.handle.net/1721.1/141310
dc.description.abstract<jats:p>The sequence space accessible to evolving proteins can be enhanced by cellular chaperones that assist biophysically defective clients in navigating complex folding landscapes. It is also possible, at least in theory, for proteostasis mechanisms that promote strict quality control to greatly constrain accessible protein sequence space. Unfortunately, most efforts to understand how proteostasis mechanisms influence evolution rely on artificial inhibition or genetic knockdown of specific chaperones. The few experiments that perturb quality control pathways also generally modulate the levels of only individual quality control factors. Here, we use chemical genetic strategies to tune proteostasis networks via natural stress response pathways that regulate the levels of entire suites of chaperones and quality control mechanisms. Specifically, we upregulate the unfolded protein response (UPR) to test the hypothesis that the host endoplasmic reticulum (ER) proteostasis network shapes the sequence space accessible to human immunodeficiency virus-1 (HIV-1) envelope (Env) protein. Elucidating factors that enhance or constrain Env sequence space is critical because Env evolves extremely rapidly, yielding HIV strains with antibody- and drug-escape mutations. We find that UPR-mediated upregulation of ER proteostasis factors, particularly those controlled by the IRE1-XBP1s UPR arm, globally reduces Env mutational tolerance. Conserved, functionally important Env regions exhibit the largest decreases in mutational tolerance upon XBP1s induction. Our data indicate that this phenomenon likely reflects strict quality control endowed by XBP1s-mediated remodeling of the ER proteostasis environment. Intriguingly, and in contrast, specific regions of Env, including regions targeted by broadly neutralizing antibodies, display enhanced mutational tolerance when XBP1s is induced, hinting at a role for host proteostasis network hijacking in potentiating antibody escape. These observations reveal a key function for proteostasis networks in decreasing instead of expanding the sequence space accessible to client proteins, while also demonstrating that the host ER proteostasis network profoundly shapes the mutational tolerance of Env in ways that could have important consequences for HIV adaptation.</jats:p>en_US
dc.language.isoen
dc.publisherPublic Library of Science (PLoS)en_US
dc.relation.isversionof10.1371/journal.pbio.3001569en_US
dc.rightsCreative Commons Attribution 4.0 International licenseen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.sourcePLoSen_US
dc.titleThe endoplasmic reticulum proteostasis network profoundly shapes the protein sequence space accessible to HIV envelopeen_US
dc.typeArticleen_US
dc.identifier.citationYoon, Jimin, Nekongo, Emmanuel E, Patrick, Jessica E, Hui, Tiffani, Phillips, Angela M et al. 2022. "The endoplasmic reticulum proteostasis network profoundly shapes the protein sequence space accessible to HIV envelope." PLOS Biology, 20 (2).
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistry
dc.relation.journalPLOS Biologyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2022-03-18T18:54:45Z
dspace.orderedauthorsYoon, J; Nekongo, EE; Patrick, JE; Hui, T; Phillips, AM; Ponomarenko, AI; Hendel, SJ; Sebastian, RM; Zhang, YM; Butty, VL; Ogbunugafor, CB; Lin, Y-S; Shoulders, MDen_US
dspace.date.submission2022-03-18T18:54:47Z
mit.journal.volume20en_US
mit.journal.issue2en_US
mit.licensePUBLISHER_CC
mit.metadata.statusAuthority Work and Publication Information Neededen_US


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