Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
Sci Adv. 2024 Oct 4;10(40):eado8540. doi: 10.1126/sciadv.ado8540.
Certain human papillomaviruses (HPVs) are etiological agents for several anogenital and oropharyngeal cancers. During initial infection, HPV16, the most prevalent cancer-causing type, specifically interacts with heparan sulfates (HSs), not only enabling initial cell attachment but also triggering a crucial conformational change in viral capsids termed structural activation. It is unknown, whether these HPV16-HS interactions depend on HS sulfation patterns. Thus, we probed potential roles of HS sulfations using cell-based functional and physicochemical assays, including single-molecule force spectroscopy. Our results demonstrate that N-sulfation of HS is crucial for virus binding and structural activation by providing high-affinity sites, and that additional 6O-sulfation is required to mechanically stabilize the interaction, whereas 2O-sulfation and 3O-sulfation are mostly dispensable. Together, our findings identify the contribution of HS sulfation patterns to HPV16 binding and structural activation and reveal how distinct sulfation groups of HS synergize to facilitate HPV16 entry, which, in turn, likely influences the tropism of HPVs.
某些人类乳头瘤病毒（HPV）是几种肛门生殖器和口咽癌的病因。在初次感染期间，最常见的致癌类型 HPV16 特异性地与肝素硫酸盐（HS）相互作用，不仅能够实现初始细胞附着，还能触发病毒衣壳的关键构象变化，称为结构激活。目前尚不清楚这些 HPV16-HS 相互作用是否取决于 HS 硫酸化模式。因此，我们使用基于细胞的功能和物理化学测定法，包括单分子力谱法，探究了 HS 硫酸化的潜在作用。我们的结果表明，HS 的 N-硫酸化对于病毒结合和结构激活至关重要，因为它提供了高亲和力结合位点，而额外的 6O-硫酸化对于机械稳定相互作用是必需的，而 2O-硫酸化和 3O-硫酸化大多是可有可无的。总之，我们的发现确定了 HS 硫酸化模式对 HPV16 结合和结构激活的贡献，并揭示了 HS 的不同硫酸化基团如何协同促进 HPV16 的进入，这反过来又可能影响 HPV 的嗜性。
