PDF(Pubmed)
Abstract：
Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or alternate LT open reading frames (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1). Following activation, NF-κB dimers bind the MCPyV noncoding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB- and NTAR-dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.
摘要：
多瘤病毒很小，可导致癌症的环状dsDNA病毒。多瘤病毒早期转录本的可变剪接产生大的和小的肿瘤抗原（LT，ST）在病毒复制和肿瘤发生中起重要作用。一些多瘤病毒还表达中间肿瘤抗原（MT）或替代LT开放阅读框（ALTO），它们在进化上是相关的，但有不同的基因结构。MT是早期转录物的剪接变体,而ALTO在备选阅读框中被套印在LT转录物的第二个外显子上,并通过备选起始密码子翻译。默克尔细胞多瘤病毒（MCPyV），唯一导致癌症的人类多瘤病毒，编码ALTO，但其在病毒生命周期和肿瘤发生中的作用仍然难以捉摸。这里,我们显示MCPyVALTO作为肿瘤抑制因子，在默克尔细胞癌（MCC）中沉默。在MCC细胞中挽救ALTO诱导生长停滞并激活NF-κB信号传导。ALTO通过两个N端激活区（NTAR1+2）结合SQSTM1和TRAF2&3激活NF-κB，类似爱泼斯坦-巴尔病毒（EBV）潜伏膜蛋白1（LMP1）。激活后,NF-κB二聚体结合MCPyV非编码控制区(NCCR)并下调早期转录。超越MCPyV,NTAR基序在其他多瘤病毒ALTO中保守，激活NF-κB信号,但缺少没有的MT。此外，多瘤病毒ALTO以NF-κB和NTAR依赖性方式下调各自的病毒早期转录。我们的发现表明，ALTO进化为抑制病毒复制并促进病毒潜伏期，并且MCPyVALTO必须沉默才能发展为MCC。
