Neurovirology Project, Tokyo Metropolitan Institute of Medical Science, 156-8506, Tokyo, Japan.
Department of Pathology, University of Malaya, 59100, Kuala Lumpur, Malaysia.
Biol Open. 2022 Sep 15;11(9). doi: 10.1242/bio.059469. Epub 2022 Sep 13.
Enterovirus 71 (EV71) is one of the causative agents of hand-foot-and-mouth disease, which in some circumstances could lead to severe neurological diseases. Despite of its importance for human health, little is known about the early stages of EV71 infection. EV71 starts uncoating with its receptor, human scavenger receptor B2 (hSCARB2), at low pH. We show that EV71 was not targeted to lysosomes in human rhabdomyosarcoma cells overexpressing hSCARB2 and that the autophagic pathway is not essential for EV71 productive uncoating. Instead, EV71 was efficiently uncoated 30 min after infection in late endosomes (LEs) containing hSCARB2, mannose-6-phosphate receptor (M6PR), RAB9, bis(monoacylglycero)phosphate and lysosomal associated membrane protein 2 (LAMP2). Furthering the notion that mature LEs are crucial for EV71 uncoating, cation-dependent (CD)-M6PR knockdown impairs EV71 infection. Since hSCARB2 interacts with cation-independent (CI)-M6PR through M6P-binding sites and CD-M6PR also harbor a M6P-binding site, CD-M6PR is likely to play important roles in EV71 uncoating in LEs.
肠道病毒 71 型（EV71）是手足口病的病原体之一，在某些情况下可导致严重的神经系统疾病。尽管它对人类健康很重要，但人们对 EV71 感染的早期阶段知之甚少。EV71 在低 pH 值下与受体——人清道夫受体 B2（hSCARB2）一起开始脱壳。我们发现，在过度表达 hSCARB2 的人横纹肌肉瘤细胞中，EV71 不会被靶向到溶酶体，并且自噬途径对于 EV71 的有效脱壳并不必要。相反，在含有 hSCARB2、甘露糖-6-磷酸受体（M6PR）、RAB9、双（单酰基甘油）磷酸和溶酶体相关膜蛋白 2（LAMP2）的晚期内体（LE）中，EV71 在感染后 30 分钟即可有效脱壳。进一步的研究表明，成熟的 LE 对于 EV71 脱壳至关重要，阳离子依赖性（CD）-M6PR 的敲低会损害 EV71 的感染。由于 hSCARB2 通过 M6P 结合位点与阳离子非依赖性（CI）-M6PR 相互作用，而 CD-M6PR 也含有一个 M6P 结合位点，因此 CD-M6PR 很可能在 LE 中的 EV71 脱壳中发挥重要作用。
