Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry

Susan A. Leonhardt, Michael D. Purdy, Jonathan R. Grover, Ziwei Yang, Sandra Poulos, William E. McIntire, Elizabeth A. Tatham, Satchal K. Erramilli, Kamil Nosol, Kin Kui Lai, Shilei Ding, Maolin Lu, Pradeep D. Uchil, Andrés Finzi, Alan Rein, Anthony A. Kossiakoff, Walther Mothes () and Mark Yeager ()
Additional contact information
Susan A. Leonhardt: University of Miami
Michael D. Purdy: University of Virginia School of Medicine
Jonathan R. Grover: Yale University School of Medicine
Ziwei Yang: Yale University School of Medicine
Sandra Poulos: University of Virginia School of Medicine
William E. McIntire: University of Miami
Elizabeth A. Tatham: University of Virginia School of Medicine
Satchal K. Erramilli: University of Chicago
Kamil Nosol: University of Chicago
Kin Kui Lai: National Cancer Institute, National Institutes of Health
Shilei Ding: Centre de Recherche du CHUM (CRCHUM)
Maolin Lu: Yale University School of Medicine
Pradeep D. Uchil: Yale University School of Medicine
Andrés Finzi: Centre de Recherche du CHUM (CRCHUM)
Alan Rein: National Cancer Institute, National Institutes of Health
Anthony A. Kossiakoff: University of Chicago
Walther Mothes: Yale University School of Medicine
Mark Yeager: University of Miami

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39262-2

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