Abstract
Tripartite motif 14 (TRIM14) was reported to function as a mitochondrial signaling adaptor in mediating innate immune responses. However, the involvement of TRIM14 in host defense against viral infection and molecular mechanisms remain unclear. Here, we demonstrated that enforced expression of TRIM14 could potently inhibit the infection and replication of HCV in hepatocytes, whereas TRIM14 knockout cells became more susceptible to HCV infection. Interestingly, further experiments revealed that such anti-HCV activity was independent of activating the NF-κB or interferon pathways but required the C-terminal SPRY domain of no signaling capacity. In searching for mechanisms how TRIM14 exerts its antiviral function we found that TRIM14 interacted with HCV encoded non-structural protein NS5A and could strongly induce its degradation dependent on the NS5A1 subdomain. Interestingly extensive domain mapping analyses revealed that NS5A degradation was mediated by the highly conserved SPRY domain of TRIM14, which might involve the K48 ubiquitination pathway. Collectively, our work uncovered a new mechanism responsible for host defense against HCV infection, and could potentially aid the development of novel anti-HCV therapeutics.
Highlights
Hepatitis C virus (HCV), a single-stranded RNA, belongs to the Flaviviridae family, is an enveloped virus with a 9.6-kb genome[1]
The plasmid expressing Tripartite motif 14 (TRIM14) was transfected into Huh[7] cells, the cells were infected with HCV GFP reporter virus (HCV-GFP), HCV replication was analyzed and measured by FACS based on GFP signals
These results suggest that TRIM14 inhibits the replication of HCV and restricts the HCV infection
Summary
Hepatitis C virus (HCV), a single-stranded RNA, belongs to the Flaviviridae family, is an enveloped virus with a 9.6-kb genome[1]. D2 can promote NS5A dimerization and it has the potential to play off against the innate immune response caused by HCV infection[12,13]. TRIM6 can interact with hepatitis B virus (HBV) core promoter to inhibit HBV RNA transcription[26]. The authors found that TRIM14 could inhibit VSV virus replication by enhancing the type I interferon pathway and NF-κB production. The function of TRIM14 on HCV infection and replication in liver cells and the mechanism underline that are currently unknown. We found that the inhibitory function of TRIM14 to HCV replication is independent of its activity of up-regulate the type I interferon pathway and NF-κB production. We demonstrated that TRIM14 interacted with NS5A and induced NS5A degradation in a dose dependent manner and was mainly mediated by SPRY domain
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