Show simple item record

dc.contributor.authorLee, J.-G.
dc.contributor.authorHuang, W.
dc.contributor.authorLee, H.
dc.contributor.authorvan de Leemput, J.en_US
dc.contributor.authorKane, M.A.en_US
dc.contributor.authorHan, Z.en_US
dc.date.accessioned2021-04-12T16:16:38Z
dc.date.available2021-04-12T16:16:38Z
dc.date.issued2021-03-25
dc.identifier.urihttp://hdl.handle.net/10713/15161
dc.description.abstractBackground: SARS-CoV-2 causes COVID-19 which has a widely diverse disease profile. The mechanisms underlying its pathogenicity remain unclear. We set out to identify the SARS-CoV-2 pathogenic proteins that through host interactions cause the cellular damages underlying COVID-19 symptomatology. Methods: We examined each of the individual SARS-CoV-2 proteins for their cytotoxicity in HEK 293 T cells and their subcellular localization in COS-7 cells. We also used Mass-Spec Affinity purification to identify the host proteins interacting with SARS-CoV-2 Orf6 protein and tested a drug that could inhibit a specific Orf6 and host protein interaction. Results: We found that Orf6, Nsp6 and Orf7a induced the highest toxicity when over-expressed in human 293 T cells. All three proteins showed membrane localization in COS-7 cells. We focused on Orf6, which was most cytotoxic and localized to the endoplasmic reticulum, autophagosome and lysosomal membranes. Proteomics revealed Orf6 interacts with nucleopore proteins (RAE1, XPO1, RANBP2 and nucleoporins). Treatment with Selinexor, an FDA-approved inhibitor for XPO1, attenuated Orf6-induced cellular toxicity in human 293 T cells. Conclusions: Our study revealed Orf6 as a highly pathogenic protein from the SARS-CoV-2 genome, identified its key host interacting proteins, and Selinexor as a drug candidate for directly targeting Orf6 host protein interaction that leads to cytotoxicity. Copyright 2021, The Author(s).en_US
dc.description.sponsorshipThis work was supported, in part, by the University of Maryland Baltimore Institute for Clinical and Translational Research (UMB ICTR) COVID-19 Accelerated Translational Incubator Pilot (ATIP) grant to Dr. Han, and the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014).en_US
dc.description.urihttps://doi.org/10.1186/s13578-021-00568-7en_US
dc.language.isoen_USen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofCell and Bioscience
dc.subjectSelinexoren_US
dc.subject.meshSARS-CoV-2--geneticsen_US
dc.subject.meshSARS-CoV-2--pathogenicityen_US
dc.titleCharacterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexoren_US
dc.typeArticleen_US
dc.identifier.doi10.1186/s13578-021-00568-7


This item appears in the following Collection(s)

Show simple item record