The Mus musculus Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis.
The Mus musculus Papillomavirus Type 1 E7 Protein Binds to the Retinoblastoma Tumor Suppressor: Implications for Viral Pathogenesis.
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DOI：
10.1128/mbio.02277-21
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发表时间：
2021-08-31
期刊：
影响因子：
6.4
通讯作者：
Munger K
中科院分区：
文献类型：
--
作者：
Wei T;Grace M;Uberoi A;Romero-Masters JC;Lee D;Lambert PF;Munger K
乳头瘤病毒的物种特异性一直是在常见模式生物中进行体内发病机制研究的重要障碍。小鼠肌肉乳头状瘤病毒1型(MmuPV1)可引起皮肤乳头状瘤，在实验室小鼠中可发展为鳞状细胞癌。乳头瘤病毒E6和E7基因编码的蛋白质建立和维持一个细胞环境，允许在生长受阻的终末分化的角质形成细胞中合成病毒基因组和病毒后代。E6和E7蛋白通过与关键的细胞调节蛋白结合并在功能上重新编程来提供这种活性。MmuPV1 E7蛋白缺乏典型的LXCXE基序，该基序介导多种病毒癌蛋白与细胞视网膜母细胞瘤肿瘤抑制蛋白RB1的结合。然而，我们的蛋白质组实验表明，MmuPV1 E7仍然与RB1相互作用。我们发现MmuPV1 E7通过其C末端与RB1的C末端结构域相互作用。MmuPV1 E7与RB1的结合没有引起E2F调节的细胞基因的显著激活。MmuPV1 E7的表达对乳头状瘤的形成是必不可少的。实验性感染表达与RB1结合缺陷的E7突变体的MmuPV1小鼠，导致起病延迟，发病率较低，乳头状瘤体积较小。我们的结果表明，MmuPV1E7基因是必需的，靶向Rb1的非规范活动，而不是Rb1的S调节E2F调节基因表达的能力，在乳头状瘤病毒介导的致病机制中起到了作用。
The species specificity of papillomaviruses has been a significant roadblock for performing in vivo pathogenesis studies in common model organisms. The Mus musculus papillomavirus type 1 (MmuPV1) causes cutaneous papillomas that can progress to squamous cell carcinomas in laboratory mice. The papillomavirus E6 and E7 genes encode proteins that establish and maintain a cellular milieu that allows for viral genome synthesis and viral progeny synthesis in growth-arrested, terminally differentiated keratinocytes. The E6 and E7 proteins provide this activity by binding to and functionally reprogramming key cellular regulatory proteins. The MmuPV1 E7 protein lacks the canonical LXCXE motif that mediates the binding of multiple viral oncoproteins to the cellular retinoblastoma tumor suppressor protein, RB1. Our proteomic experiments, however, revealed that MmuPV1 E7 still interacts with RB1. We show that MmuPV1 E7 interacts through its C terminus with the C-terminal domain of RB1. Binding of MmuPV1 E7 to RB1 did not cause significant activation of E2F-regulated cellular genes. MmuPV1 E7 expression was shown to be essential for papilloma formation. Experimental infection of mice with MmuPV1 expressing an E7 mutant that is defective for binding to RB1 caused delayed onset, lower incidence, and smaller sizes of papillomas. Our results demonstrate that the MmuPV1 E7 gene is essential and that targeting noncanonical activities of RB1, which are independent of RB1’s ability to modulate the expression of E2F-regulated genes, contribute to papillomavirus-mediated pathogenesis.