de Souza Cardoso Ricardo, Murakami Tomoyuki, Jacobovitz Binyamin, Veatch Sarah L, Ono Akira
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Biophysics, University of Michigan, Ann Arbor, Michigan, USA.
bioRxiv. 2024 Sep 5:2024.09.05.611432. doi: 10.1101/2024.09.05.611432.
Determinants regulating sorting of host transmembrane proteins at sites of enveloped virus assembly on the plasma membrane (PM) remain poorly understood. Here, we demonstrate for the first time that PM acidic phospholipid PIP2 regulates such sorting into an enveloped virus, HIV-1. Incorporation of CD43, PSGL-1, and CD44 into HIV-1 particles is known to have profound effects on viral spread; however, the mechanisms promoting their incorporation were unknown. We found that depletion of cellular PIP2 blocks the incorporation of CD43, PSGL-1, and CD44 into HIV-1 particles. Expansion microscopy revealed that PIP2 depletion diminishes nanoscale co-clustering between viral structural protein Gag and the three transmembrane proteins at PM and that Gag induces PIP2 enrichment around itself. CD43, PSGL-1, and CD44 also increased local PIP2 density, revealing their PIP2 affinity. Altogether, these results support a new mechanism where local enrichment of an acidic phospholipid drives co-clustering between viral structural and cellular transmembrane proteins, thereby modulating the content, and hence the fate, of progeny virus particles.
调节宿主跨膜蛋白在质膜（PM）上包膜病毒组装位点分选的决定因素仍知之甚少。在此，我们首次证明质膜酸性磷脂PIP2调节这种分选进入包膜病毒HIV-1。已知CD43、PSGL-1和CD44掺入HIV-1颗粒对病毒传播有深远影响；然而，促进它们掺入的机制尚不清楚。我们发现细胞PIP2的消耗会阻止CD43、PSGL-1和CD44掺入HIV-1颗粒。扩展显微镜显示，PIP2的消耗减少了质膜上病毒结构蛋白Gag与这三种跨膜蛋白之间的纳米级共聚集，并且Gag会诱导自身周围的PIP2富集。CD43、PSGL-1和CD44也增加了局部PIP2密度，揭示了它们对PIP2的亲和力。总之，这些结果支持了一种新机制，即酸性磷脂的局部富集驱动病毒结构蛋白和细胞跨膜蛋白之间的共聚集，从而调节子代病毒颗粒的内容物，进而影响其命运。
