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HCMV US28的第三个细胞内循环是信号和病毒重新激活所必需的

Samuel Medica^1,2, Michael Denton¹, Nicole L Diggins¹

¹Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, USA.

Journal of virology

|December 10, 2024

概括

人类细胞巨化病毒 (HCMV) US28的第三个细胞内循环 (ICL3) 中的特定残留物对于G蛋白合和下游信号传递至关重要. 这些部位的突变会从潜伏期损害病毒的活性,提供治疗点.

科学领域:

病毒学病毒学
分子生物学分子生物学
免疫学免疫学免疫学

背景情况:

人类细胞巨乳病毒 (HCMV) 建立了终身潜伏感染,重新激活对免疫功能低下的个体构成重大风险.
编码于HCMV的US28化学受体对病毒病变产生至关重要,影响延迟和重新激活,但其精确的信号机制尚不清楚.
了解US28在宿主细胞操纵中的作用对于开发针对HCMV相关疾病的策略至关重要.

研究的目的:

阐明HCMV US28受体对其功能活动至关重要的信号域.
在US28中识别特定的残留物,这些残留物介于G蛋白合和下游信号传导.
调查US28突变对病毒延迟和重新激活的影响.

主要方法:

使用局部定向突变发生来分析US28第三细胞内循环 (ICL3) 中的特定残留物.
功能性测试评估了G蛋白合,MAPK和RhoA通路激活以及受体局部化/内部化.
使用CD34+血造原生细胞 (HPC) 模型和人性化的小鼠模型研究了病毒延迟和活性.

主要成果:

在US28残留S218,K223和R225的氨酸替代物显著减弱了G蛋白合和下游信号 (MAPK,Rhoa).
这些突变没有影响US28的血局部化或内部化率.
通过ICL3突变损坏的US28信号传递导致了在体外和体外模型中因延迟而造成低效的病毒活性.

结论:

在US28 ICL3中的关键残留物是G蛋白合和下游信号的重要决定因素,调节HCMV延迟和重新激活.
针对US28的ICL3区域提供了一个潜在的策略,以抑制HCMV的重新激活和相关疾病.
这项研究提供了对由US28受体介导的HCMV病原体背后的分子机制的新见解.

关键词:

与G蛋白结合受体的受体是G蛋白结合受体.细胞巨型病毒 (cytomegalovirus) 是一种病毒.延迟时间延迟时间再激活重新激活的方法信号传导的信号传导.

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