CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Acting in <i>cis</i>
CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Acting in <i>cis</i>
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CADM1 和 CADM2 通过顺式作用触发神经病性麻疹病毒介导的膜融合
DOI：
10.1128/jvi.00528-21
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发表时间：
2021
影响因子：
5.4
通讯作者：
Yanagi Yusuke
中科院分区：
文献类型：
--
作者：
Shirogane Yuta;Takemoto Ryuichi;Suzuki Tateki;Kameda Tomonori;Nakashima Kinichi;Hashiguchi Takao;Yanagi Yusuke
麻疹病毒(Merles Virus，MeV)是副粘病毒科的一种囊膜RNA病毒，目前仍是世界范围内儿童发病和死亡的重要原因。MEV通常会导致出现皮疹的急性发热性疾病，但在极少数情况下，会持续存在于大脑中，导致进行性神经疾病，亚急性硬化性泛脑炎(SSPE)。这种疾病是致命的，目前还没有有效的治疗方法。尽管跨突触的细胞间传递被认为是MeV在大脑中传播的原因，但神经元并不表达已知的MeV受体。最近的研究表明，MeV融合蛋白(F)的超超声改变在MeV在脑内的传播中起着关键作用。然而，这种突变病毒是如何在神经元中传播的仍未得到解释。在这里，我们发现细胞黏附分子1(CADM1；也被称为IGSF4A，NECL-2和SynCAM1)和CADM2(也被称为IGSF4D，NCEL-3，SynCAM2)是使MeV能够在缺乏已知受体的细胞中引起膜融合并在神经元之间传播的宿主因子。在包膜病毒进入期间，细胞受体通常与包膜上的附着蛋白相互作用。然而，CADM1和CADM2与同一细胞膜上的MeV附着蛋白相互作用，导致融合蛋白触发和膜融合。CADM1和CADM2的敲除抑制了合胞体的形成和神经元之间的病毒传播，这两种作用都是由超音素F蛋白介导的。因此，我们的结果揭示了MeV在神经元之间跨突触传播从而导致SSPE的分子机制(受体模拟顺式作用融合触发)。重要措施病毒(MeV)是一种囊膜RNA病毒，是麻疹的病原体，至今仍是全球儿童发病率和死亡率的重要原因。在急性感染几年后，脑部持续的MeV感染会导致一种致命的进行性神经疾病，亚急性硬化性全脑炎(SSPE)。然而，MeV如何在神经元中传播，主要受SSPE的影响，在很大程度上仍不清楚。在这项研究中，我们证明了细胞黏附分子1(CADM1)和CADM2是使MeV在神经元之间传播的宿主因子。在包膜病毒进入期间，细胞受体通常与病毒膜(包膜)上的附着蛋白相互作用。值得注意的是，CADM1和CADM2与同一膜上的MeV附着蛋白相互作用，触发融合蛋白并引起膜融合，就像病毒受体通常作用于内含子一样。仔细的筛查可能会导致在其他病毒中出现更多这样的“受体模仿顺式作用融合触发”的例子。
Measles virus (MeV), an enveloped RNA virus in the familyParamyxoviridae, is still an important cause of childhood morbidity and mortality worldwide. MeV usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). The disease is fatal, and no effective therapy is currently available. Although transsynaptic cell-to-cell transmission is thought to account for MeV propagation in the brain, neurons do not express the known receptors for MeV. Recent studies have shown that hyperfusogenic changes in the MeV fusion (F) protein play a key role in MeV propagation in the brain. However, how such mutant viruses spread in neurons remains unexplained. Here, we show that cell adhesion molecule 1 (CADM1; also known as IGSF4A, Necl-2, and SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors that enable MeV to cause membrane fusion in cells lacking the known receptors and to spread between neurons. During enveloped virus entry, a cellular receptor generally interacts intranswith the attachment protein on the envelope. However, CADM1 and CADM2 interact inciswith the MeV attachment protein on the same cell membrane, causing the fusion protein triggering and membrane fusion. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons that are both mediated by hyperfusogenic F proteins. Thus, our results unravel the molecular mechanism (receptor-mimickingcis-acting fusion triggering) by which MeV spreads transsynaptically between neurons, thereby causing SSPE.IMPORTANCEMeasles virus (MeV), an enveloped RNA virus, is the causative agent of measles, which is still an important cause of childhood morbidity and mortality worldwide. Persistent MeV infection in the brain causes a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. However, how MeV spreads in neurons, which are mainly affected in SSPE, remains largely unknown. In this study, we demonstrate that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV spread between neurons. During enveloped virus entry, a cellular receptor generally interacts intranswith the attachment protein on the viral membrane (envelope). Remarkably, CADM1 and CADM2 interact inciswith the MeV attachment protein on the same membrane, triggering the fusion protein and causing membrane fusion, as viral receptors usually do intrans. Careful screening may lead to more examples of such “receptor-mimickingcis-acting fusion triggering” in other viruses.