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Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry

The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). Here, we determine cryoEM maps of full-length human SE...

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Autores principales: Leonhardt, Susan A., Purdy, Michael D., Grover, Jonathan R., Yang, Ziwei, Poulos, Sandra, McIntire, William E., Tatham, Elizabeth A., Erramilli, Satchal K., Nosol, Kamil, Lai, Kin Kui, Ding, Shilei, Lu, Maolin, Uchil, Pradeep D., Finzi, Andrés, Rein, Alan, Kossiakoff, Anthony A., Mothes, Walther, Yeager, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359404/
https://www.ncbi.nlm.nih.gov/pubmed/37474505
http://dx.doi.org/10.1038/s41467-023-39262-2
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author Leonhardt, Susan A.
Purdy, Michael D.
Grover, Jonathan R.
Yang, Ziwei
Poulos, Sandra
McIntire, William E.
Tatham, Elizabeth A.
Erramilli, Satchal K.
Nosol, Kamil
Lai, Kin Kui
Ding, Shilei
Lu, Maolin
Uchil, Pradeep D.
Finzi, Andrés
Rein, Alan
Kossiakoff, Anthony A.
Mothes, Walther
Yeager, Mark
author_facet Leonhardt, Susan A.
Purdy, Michael D.
Grover, Jonathan R.
Yang, Ziwei
Poulos, Sandra
McIntire, William E.
Tatham, Elizabeth A.
Erramilli, Satchal K.
Nosol, Kamil
Lai, Kin Kui
Ding, Shilei
Lu, Maolin
Uchil, Pradeep D.
Finzi, Andrés
Rein, Alan
Kossiakoff, Anthony A.
Mothes, Walther
Yeager, Mark
author_sort Leonhardt, Susan A.
collection PubMed
description The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). Here, we determine cryoEM maps of full-length human SERINC3 and an ICL4 deletion construct, which reveal that hSERINC3 is comprised of two α-helical bundles connected by a ~ 40-residue, highly tilted, “crossmember” helix. The design resembles non-ATP-dependent lipid transporters. Consistently, purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. Furthermore, SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity, with similar results in MLV. SERINC effects in HIV-1 and MLV are counteracted by Nef and GlycoGag, respectively. Our results demonstrate that SERINCs are membrane transporters that flip lipids, resulting in a loss of membrane asymmetry that is strongly correlated with changes in Env conformation and loss of infectivity.
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spelling pubmed-103594042023-07-22 Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry Leonhardt, Susan A. Purdy, Michael D. Grover, Jonathan R. Yang, Ziwei Poulos, Sandra McIntire, William E. Tatham, Elizabeth A. Erramilli, Satchal K. Nosol, Kamil Lai, Kin Kui Ding, Shilei Lu, Maolin Uchil, Pradeep D. Finzi, Andrés Rein, Alan Kossiakoff, Anthony A. Mothes, Walther Yeager, Mark Nat Commun Article The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). Here, we determine cryoEM maps of full-length human SERINC3 and an ICL4 deletion construct, which reveal that hSERINC3 is comprised of two α-helical bundles connected by a ~ 40-residue, highly tilted, “crossmember” helix. The design resembles non-ATP-dependent lipid transporters. Consistently, purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. Furthermore, SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity, with similar results in MLV. SERINC effects in HIV-1 and MLV are counteracted by Nef and GlycoGag, respectively. Our results demonstrate that SERINCs are membrane transporters that flip lipids, resulting in a loss of membrane asymmetry that is strongly correlated with changes in Env conformation and loss of infectivity. Nature Publishing Group UK 2023-07-20 /pmc/articles/PMC10359404/ /pubmed/37474505 http://dx.doi.org/10.1038/s41467-023-39262-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Leonhardt, Susan A.
Purdy, Michael D.
Grover, Jonathan R.
Yang, Ziwei
Poulos, Sandra
McIntire, William E.
Tatham, Elizabeth A.
Erramilli, Satchal K.
Nosol, Kamil
Lai, Kin Kui
Ding, Shilei
Lu, Maolin
Uchil, Pradeep D.
Finzi, Andrés
Rein, Alan
Kossiakoff, Anthony A.
Mothes, Walther
Yeager, Mark
Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
title Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
title_full Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
title_fullStr Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
title_full_unstemmed Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
title_short Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry
title_sort antiviral hiv-1 serinc restriction factors disrupt virus membrane asymmetry
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359404/
https://www.ncbi.nlm.nih.gov/pubmed/37474505
http://dx.doi.org/10.1038/s41467-023-39262-2
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