Department of Cell and Developmental Biology, University of Michigan Medical School Ann Arbor, Michigan, United States of America.
Department of Biological Chemistry, University of Michigan Medical School Ann Arbor, Michigan, United States of America.
PLoS Pathog. 2022 Sep 6;18(9):e1010824. doi: 10.1371/journal.ppat.1010824. eCollection 2022 Sep.
Nuclear entry represents the final and decisive infection step for most DNA viruses, although how this is accomplished by some viruses is unclear. Polyomavirus SV40 transports from the cell surface through the endosome, the endoplasmic reticulum, and the cytosol from where it enters the nucleus to cause infection. Here we elucidate the nuclear entry mechanism of SV40. Our results show that cytosol-localized SV40 is targeted to the nuclear envelope by directly engaging Nesprin-2 of the linker of nucleoskeleton and cytoskeleton (LINC) nuclear membrane complex. Additionally, we identify the NUP188 subunit of the nuclear pore complex (NPC) as a new Nesprin-2-interacting partner. This physical proximity positions the NPC to capture SV40 upon release from Nesprin-2, enabling the channel to facilitate nuclear translocation of the virus. Strikingly, SV40 disassembles during nuclear entry, generating a viral genome-VP1-VP3 subcomplex that efficiently crosses the NPC to enter the nucleus. Our results reveal how two major nuclear membrane protein complexes are exploited to promote targeting and translocation of a virus into the nucleus.
核内进入是大多数 DNA 病毒完成感染的最后和决定性步骤，尽管某些病毒如何完成这一步骤尚不清楚。多瘤病毒 SV40 通过内体、内质网和细胞质从细胞表面运输，然后进入细胞核引发感染。在此，我们阐明了 SV40 的核内进入机制。我们的结果表明，定位于细胞质的 SV40 通过直接与核骨架和细胞质连接体（LINC）核膜复合物的 Nesprin-2 结合，被靶向到核膜。此外，我们鉴定了核孔复合物（NPC）的 NUP188 亚基是 Nesprin-2 的一个新的相互作用伙伴。这种物理接近使 NPC 能够在从 Nesprin-2 释放后捕获 SV40，从而使通道能够促进病毒的核内转运。引人注目的是，SV40 在核内进入过程中解体，生成一个病毒基因组-VP1-VP3 亚复合物，该亚复合物有效地穿过 NPC 进入细胞核。我们的结果揭示了两种主要的核膜蛋白复合物如何被利用来促进病毒靶向和转运到细胞核内。
