Regulation and Function of Human Polyomavirus circular RNAs

越来越多的环状RNA(CircRNAs)被发现由病毒和 然而，大多数CircRNAs的生理意义仍不清楚。 我们的长期目标是利用人类多瘤病毒(HPYV)来了解 CircRNA，并利用这一知识开发新的病毒诊断和治疗方法 疾病。我们认为许多病毒CircRNA具有编码RNA的功能，这些RNA具有不同于 来自同一基因的线状RNA拼接而成。具体地说，我们的中心假设是默克尔细胞 多瘤病毒和棘毛发育不良多瘤病毒编码环状ALTO RNA，CircALTO，即 都被翻译成ALTO，然后ALTO调节受感染宿主细胞的转录。此模型基于 初步研究表明，MCPyV和TSPyV早期区域都有效地产生了环状ALTO，这 在体外被翻译成ALTO蛋白。MCPyV CircALTO作为转录反式激活因子发挥作用 可以诱导先前在DNA中涉及的多个基因和途径的转录 病毒感染。我们进一步证明了从MCPyV早期区域表达的miRNA miR-M1， 负向调节ALTO和ALTO水平。扩展和验证此模型将代表一个 我们对CircRNA功能和调控的理解取得了突破性的进展。这项提案将是 组织为两个目标：1)确定MCPyV环状病毒形成的调节因素和它的 MCPyV miR-M1 miRNA的抑制作用，并确定这些因素如何影响病毒复制和 持续；2)确定MCPyV ALTO如何调节宿主细胞转录以及ALTO是否影响 On转录在TSPyV中是保守的。我们将与具有以下专业知识的病毒学家合作 多瘤病毒和miRNA生物学，以完成拟议的目标。完成本提案将不会 不仅扩大了CircRNAs在病毒学和细胞信号转导中的相关性，而且还显着促进了我们的 了解人类多瘤病毒的发病机制。

An increasing number of circular RNAs (circRNAs) have been found to be expressed by both viruses and human host cells during viral infection, yet the physiological significance of most circRNAs remains unclear. Our long-term goal is to use human polyomaviruses (HPyVs) to understand the regulation and function of circRNAs and to leverage this knowledge towards developing new diagnostics and treatments for viral diseases. We propose that many viral circRNAs function as coding RNAs that have distinct properties from linear RNAs spliced from the same gene. Specifically, our central hypothesis is that Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus encodes circular ALTO RNAs, circALTOs, that are translated to ALTO, which then modulates transcription in infected host cells. This model is based on preliminary studies showing that both MCPyV and TSPyV early regions efficiently generate circALTO, which are translated into ALTO protein in vitro. MCPyV circALTO functions as a transcriptional transactivator that can induce the transcription of multiple genes and pathways that have previously been implicated in DNA virus infections. We further demonstrate that a miRNA expressed from the MCPyV early region, miR-M1, negatively regulates circALTO and ALTO levels. Extending and validating this model would represent a ground-breaking advance in our understanding of circRNA function and regulation. This proposal will be organized into two aims: 1) Identify the factors that regulate the formation of MCPyV circALTO and its inhibition by the MCPyV miR-M1 miRNA and determine how these factors impact viral replication and persistence; 2) Determine how MCPyV ALTO modulates host cell transcription and whether ALTO’s effects on transcription are conserved in TSPyV. We will collaborate with virologists with expertise in polyomaviruses and miRNA biology to complete the proposed aims. Completion of this proposal will not only expand the relevance of circRNAs in virology and cell signaling but also significantly advance our understanding of the pathogenesis of human polyomaviruses.