Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL, Utrecht, The Netherlands.
Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
Nat Commun. 2019 Jul 18;10(1):3171. doi: 10.1038/s41467-019-11256-z.
Enteroviruses are a major cause of human disease. Adipose-specific phospholipase A2 (PLA2G16) was recently identified as a pan-enterovirus host factor and potential drug target. In this study, we identify a possible mechanism of PLA2G16 evasion by employing a dual glycan receptor-binding enterovirus D68 (EV-D68) strain. We previously showed that this strain does not strictly require the canonical EV-D68 receptor sialic acid. Here, we employ a haploid screen to identify sulfated glycosaminoglycans (sGAGs) as its second glycan receptor. Remarkably, engagement of sGAGs enables this virus to bypass PLA2G16. Using cryo-EM analysis, we reveal that, in contrast to sialic acid, sGAGs stimulate genome release from virions via structural changes that enlarge the putative openings for genome egress. Together, we describe an enterovirus that can bypass PLA2G16 and identify additional virion destabilization as a potential mechanism to circumvent PLA2G16.
肠道病毒是人类疾病的主要病因。脂肪组织特异性磷酸酶 A2（PLA2G16）最近被确定为一种泛肠道病毒宿主因子和潜在的药物靶点。在这项研究中，我们通过使用双糖受体结合肠道病毒 D68（EV-D68）株来鉴定 PLA2G16 逃避的可能机制。我们之前表明，该菌株并不严格需要经典的 EV-D68 受体唾液酸。在这里，我们采用单倍体筛选来鉴定硫酸化糖胺聚糖（sGAG）作为其第二个糖受体。值得注意的是，sGAG 的结合使该病毒能够绕过 PLA2G16。通过冷冻电镜分析，我们揭示了与唾液酸相反，sGAG 通过结构变化刺激病毒粒子从基因组中释放，从而扩大了推测的基因组出口的开口。总之，我们描述了一种可以绕过 PLA2G16 的肠道病毒，并确定了额外的病毒粒子不稳定化作为绕过 PLA2G16 的潜在机制。
