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bioRxiv · 10.1101/2024.12.28.630612

PSGL-1 excludes HIV Env from virion surface through spatial hindrance involving structural folding of the decameric repeats (DR)

Tiwari, S.·Delfing, B. M.·Han, Y.·Lockhart, C.·Haikerwal, A.·Waheed, A. A.·Freed, E. O.·Jafri, M. S.·Klimov, D.·Wu, Y.
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Abstract

P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like surface glycoprotein, is primarily expressed on lymphoid and myeloid cells. PSGL-1 has recently been identified as an HIV restriction factor, blocking HIV infectivity mainly through virion incorporation that sterically hinders virion attachment to target cells. PSGL-1 also inhibits HIV Env incorporation into virions. However, the molecular mechanisms of PSGL-1-mediated Env exclusion remained unclear. Here, we investigated the role of PSGL-1s extracellular (EC) and intracellular (IC) domains in Env exclusion. We demonstrate that both EC and IC are important for Env exclusion; when EC was deleted, PSGL-1 completely lost its ability to inhibit Env incorporation, whereas when IC was deleted, PSGL-1 partially lost this activity. In addition, when the decameric repeats (DR) were deleted from EC, PSGL-1 also lost its ability to inhibit Env incorporation. Sequential DR deletion mutagenesis further demonstrated that a minimum of 9 DRs is necessary for Env exclusion. Molecular modeling of the DR structure revealed that PSGL-1 mutants with 7 or fewer DRs pose as an extended "rod-like" structure, whereas those with 9 or more DRs collapse into a "coil-like" structure that spatially excludes Env. Our studies suggest a model in which Env exclusion involves Gag-mediated PSGL-1 targeting to the virion assembly site where DR-mediated spatial exclusion blocks Env incorporation.

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Tiwari, S., Delfing, B. M., Han, Y., Lockhart, C., Haikerwal, A., Waheed, A. A., Freed, E. O., Jafri, M. S., Klimov, D., Wu, Y.. 2024-12-28. PSGL-1 excludes HIV Env from virion surface through spatial hindrance involving structural folding of the decameric repeats (DR). https://doi.org/10.1101/2024.12.28.630612

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