Abstract
Ubiquitination plays a major role in immune regulation after viral infection. An alternatively spliced porcine E3 ubiquitin ligase RNF122 promoted PRRSV infection and upregulated in PRRSV-infected PAM cells was identified. We characterized the core promoter of RNF122, located between −550 to −470 bp upstream of the transcription start site (TSS), which displayed significant differential transcriptional activities in regulating the transcription and expression of RNF122. The transcription factor HLTF was inhibited by nsp1α and nsp7 of PRRSV, and the transcription factor E2F complex regulated by nsp9. Together, they modulated the transcription and expression of RNF122. RNF122 could mediate K63-linked ubiquitination to raise stability of PRRSV nsp4 protein and thus promote virus replication. Moreover, RNF122 also performed K27-linked and K48-linked ubiquitination of MDA5 to degrade MDA5 and inhibit IFN production, ultimately promoted virus proliferation. In this study, we illustrate a new immune escape mechanism of PRRSV that enhances self-stability and function of viral nsp4, thus, regulating RNF122 expression to antagonize IFNα/β production. The present study broadens our knowledge of PRRSV-coding protein modulating transcription, expression and modification of host protein to counteract innate immune signaling, and may provide novel insights for the development of antiviral drugs.
Highlights
IntroductionEurope and North America [1,2]
Porcine reproductive and respiratory syndrome (PRRS) has been a major threat to the worldwide swine industry even since its first outbreak in late 1980s in the continents of bothEurope and North America [1,2]
A total of 26 homologous enzymes containing RING domain E3 ubiquitin ligases in the transcriptomic data were further identified and the significantly up-regulated RING finger protein 122 (RNF122) was screened for further study. (Figure 1a)
Summary
Europe and North America [1,2] This disease often causes reproductive failure in sows and respiratory problems in pigs of all ages, leading to colossal economic losses, but no effective vaccines or anti-viral drugs are currently available [3]. 75% of the 5’-end of the genome and encode viral two important viral replicase polyproteins (pp1a and pp1ab) that are further processed into at least 16 nonstructural replicase proteins (nsps). These nsps come together to form viral replication and transcription complex (RTC) for genome replication and subgenomic RNA synthesis. Some nsps (e.g., nsp, nsp, nsp, nsp, nsp, etc.) are critical in antagonizing host innate immunity [8]
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