Abstract
The human retrovirus human T-cell leukemia virus type I (HTLV-1) infects human T cells by vertical transmission from mother to child through breast milk or horizontal transmission through blood transfusion or sexual contact. Approximately 5% of infected individuals develop adult T-cell leukemia/lymphoma (ATL) with a poor prognosis, while 95% of infected individuals remain asymptomatic for the rest of their lives, during which time the infected cells maintain a stable immortalized latent state in the body. It is not known why such a long latent state is maintained. We hypothesize that the role of functional proteins of HTLV-1 during early infection influences the phenotype of infected cells in latency. In eukaryotic cells, a mRNA quality control mechanism called nonsense-mediated mRNA decay (NMD) functions not only to eliminate abnormal mRNAs with nonsense codons but also to target virus-derived RNAs. We have reported that HTLV-1 genomic RNA is a potential target of NMD, and that Rex suppresses NMD and stabilizes viral RNA against it. In this study, we aimed to elucidate the molecular mechanism of NMD suppression by Rex using various Rex mutant proteins. We found that region X (aa20–57) of Rex, the function of which has not been clarified, is required for NMD repression. We showed that Rex binds to Upf1, which is the host key regulator to detect abnormal mRNA and initiate NMD, through this region. Rex also interacts with SMG5 and SMG7, which play essential roles for the completion of the NMD pathway. Moreover, Rex selectively binds to Upf3B, which is involved in the normal NMD complex, and replaces it with a less active form, Upf3A, to reduce NMD activity. These results revealed that Rex invades the NMD cascade from its initiation to completion and suppresses host NMD activity to protect the viral genomic mRNA.
Highlights
The results showed that nonsense-mediated mRNA decay (NMD) was repressed in pFL-MT2 transfected cells, whereas NMD repression was abolished in Rex(-)-pFL-MT-2 transfected cells (Figure 1C)
It was confirmed that there is no significant difference in the NMD inhibitory effect between mutant 10 and WT-Rex (Figure S1C). These results indicate that the arginine-rich motifs (ARM), an X region of unknown function, and at least one of the two multimerization domains are important for the function of Rex in NMD suppression
Because of its cytoplasmic localization, NMD activity in p21RexRex (Figure S1C). These results indicate that the ARM, an X region of unknown function expressing cells was not affected by Leptomycin B treatment or CRM1 overexpression, and at least one of the two multimerization domains are important for the funccompared to p27(WT)Rex (Figure 4B)
Summary
In the period 1980–1981, human T-cell leukemia virus type I (HTLV-1) was discovered as a human retrovirus in Japan and the USA, and was later shown to be the causative agent of adult T-cell leukemia/lymphoma (ATL) [1,2,3,4,5]. HTLV-1 mainly targets CD4+ T cells and causes ATL in approximately 5% of infected individuals after an incubation period of 50–60 years [6]. 95% of infected individuals remain asymptomatic throughout their lives, and infected cells maintain a stable immortalized latent state in the body for decades [7]. We hypothesize that the function of HTLV-1 viral accessory proteins from infection to transition to latency influences the phenotype of infected cells during latent infection
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