Short-Stalk Isoforms of CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Interacting with the Viral Hemagglutinin
Short-Stalk Isoforms of CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Interacting with the Viral Hemagglutinin
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DOI：
10.1128/jvi.01949-21
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发表时间：
2022-02-01
影响因子：
5.4
通讯作者：
Shirogane，Yuta
中科院分区：
文献类型：
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作者：
Takemoto，Ryuichi;Suzuki，Tateki;Shirogane，Yuta
麻疹病毒（MeV）是副粘病毒科中的一种包膜RNA病毒，通常引起急性发热性疾病，伴有皮疹，但在极少数情况下会持续存在于大脑中，引起进行性神经系统疾病，亚急性硬化性全脑炎（SSPE）。MeV具有两种包膜糖蛋白，血凝素（H）和融合（F）蛋白。H蛋白具有最初介导受体结合的头部结构域和随后将融合触发信号传递到F蛋白的茎部结构域。我们最近发现，细胞粘附分子1（CADM 1;也称为IGSF 4A，Necl-2和SynCAM 1）和CADM 2（也称为IGSF 4D，Necl-3和SynCAM 2）是宿主因子，能够通过神经致病性MeV的超致流F蛋白介导细胞-细胞膜融合以及MeV在缺乏已知受体的神经元之间传播。CADM 1和CADM 2与同一细胞膜上的H蛋白相互作用，触发超促流F蛋白介导的膜融合。通过选择性剪接产生含有不同长度的茎区的CADM 1和CADM 2的多种同种型。在这里，我们表明，只有短茎异构体的CADM 1和CADM 2主要在大脑中表达诱导hypperfusogenic F蛋白介导的膜融合。虽然已知的受体通过其头部结构域与H蛋白反式相互作用，但这些同种型可以与缺乏头部结构域的H蛋白相互作用，并可能通过其茎结构域触发膜融合。因此，我们的研究结果揭示了一个新的机制，病毒融合触发宿主因素。重要提示麻疹，急性发热性疾病与皮疹，仍然是一个重要的原因，儿童发病率和死亡率在世界范围内。麻疹病毒（MeV），麻疹的病原体，也可能导致进行性神经系统疾病，亚急性硬化性全脑炎（SSPE），急性感染后几年。这种疾病是致命的，没有有效的治疗方法。最近，我们报道了细胞粘附分子1（CADM 1）和CADM 2是宿主因子，使MeV细胞到细胞的神经元中的传播。这些分子与MeV附着蛋白在同一细胞膜上相互作用，触发融合蛋白并引起膜融合。已知CADM 1和CADM 2以多种剪接异构体存在。在这项研究中，我们报告说，他们的短柄异构体可以诱导膜融合的相互作用切口与病毒附着蛋白独立的受体结合头部结构域。这一发现可能具有重要的意义，强制作用融合宿主因素触发。
Measles virus (MeV), an enveloped RNA virus in the familyParamyxoviridae, 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). MeV bears two envelope glycoproteins, the hemagglutinin (H) and fusion (F) proteins. The H protein possesses a head domain that initially mediates receptor binding and a stalk domain that subsequently transmits the fusion-triggering signal to the F protein. We recently showed that cell adhesion molecule 1 (CADM1; also known as IGSF4A, Necl-2, and SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, and SynCAM2) are host factors enabling cell-cell membrane fusion mediated by hyperfusogenic F proteins of neuropathogenic MeVs as well as MeV spread between neurons lacking the known receptors. CADM1 and CADM2 interact inciswith the H protein on the same cell membrane, triggering hyperfusogenic F protein-mediated membrane fusion. Multiple isoforms of CADM1 and CADM2 containing various lengths of their stalk regions are generated by alternative splicing. Here, we show that only short-stalk isoforms of CADM1 and CADM2 predominantly expressed in the brain induce hyperfusogenic F protein-mediated membrane fusion. While the known receptors interact intranswith the H protein through its head domain, these isoforms can interact inciseven with the H protein lacking the head domain and trigger membrane fusion, presumably through its stalk domain. Thus, our results unveil a new mechanism of viral fusion triggering by host factors.IMPORTANCEMeasles, an acute febrile illness with skin rash, is still an important cause of childhood morbidity and mortality worldwide. Measles virus (MeV), the causative agent of measles, may also cause a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. The disease is fatal, and no effective therapy is available. Recently, we reported that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV cell-to-cell spread in neurons. These molecules interact inciswith the MeV attachment protein on the same cell membrane, triggering the fusion protein and causing membrane fusion. CADM1 and CADM2 are known to exist in multiple splice isoforms. In this study, we report that their short-stalk isoforms can induce membrane fusion by interacting inciswith the viral attachment protein independently of its receptor-binding head domain. This finding may have important implications forcis-acting fusion triggering by host factors.