Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis

Non-alcoholic steatohepatitis(NASH),a progressive form of non-alcoholic fatty liver disease(NAFLD),is characterised by chronic liver inflammation,which can further prog-ress into complications such as liver cirrhosis and NASH-associated hepatocellular carcinoma(HCC)and therefore has become a growing health problem worldwide.The type I interferon(IFN)signaling pathway plays a pivotal role in chronic inflammation;however,the molecular mechanisms underlying NAFLD/NASH from the perspective of innate immune response has not yet been fully explored.In this study,we elucidated the mechanisms of how innate im-mune response modulates NAFLD/NASH pathogenesis,and demonstrated that hepatocyte nu-clear factor-1alpha(HNF1A)was suppressed and the typeⅠIFN production pathway was activated in liver tissues of patients with NAFLD/NASH.Further experiments suggested that HNF1A negatively regulates the TBK1-IRF3 signaling pathway by promoting autophagic degra-dation of phosphorylated-TBK1,which constrains IFN production,thereby inhibiting the activa-tion of type I IFN signaling.Mechanistically,HNF1A interacts with the phagophore membrane protein LC3 through its LIR-docking sites,and mutations of LIRs(LIR2,LIR3,LIR4,and LIRs)block the HNF1A-LC3 interaction.In addition,HNF1A was identified not only as a novel autop-hagic cargo receptor but also to specifically induce K33-linked ubiquitin chains on TBK1 at Lys670,thereby resulting in autophagic degradation of TBK1.Collectively,our study illustrates the crucial function of the HNF1A-TBK1 signaling axis in NAFLD/NASH pathogenesis via cross-talk between autophagy and innate immunity.

Splicing factor SF3B3,a NS5-binding protein,restricts ZIKV infection by targeting GCH1

Zika virus(ZIKV),a positive-sense single-stranded RNA virus,causes congenital ZIKV syndrome in children and Guillain-Barre Syndrome(GBS)in adults.ZIKV expresses nonstructural protein 5(NS5),a large protein that is essential for viral replication.ZIKV NS5 confers the ability to evade interferon(IFN)signalling;however,the exact mechanism remains unclear.In this study,we employed affinity pull-down and liquid chromatography-tandem mass spectrometry(LC-MS/MS)analyses and found that splicing factor 3b subunit 3(SF3B3)is associated with the NS5-Flag pull-down complex through interaction with NS5.Functional assays showed that SF3B3 overexpression inhibited ZIKV replication by promoting IFN-stimulated gene(ISG)expression whereas silencing of SF3B3 inhibited expression of ISGs to promote ZIKV replication.GTP cyclohydrolase I(GCH1)is the first and ratelimiting enzyme in tetrahydrobiopterin(BH4)biosynthesis.NS5 upregulates the expression of GCH1 during ZIKV infection.And GCH1 marginally promoted ZIKV replication via the IFN pathway.Additionally,GCH1 expression is related to the regulation of SF3B3.Overexpression of the SF3B3 protein effectively reduced GCH1 protein levels,whereas SF3B3 knockdown increased its levels.These findings indicated that ZIKV NS5 binding protein SF3B3 contributed to the host immune response against ZIKV replication by modulating the expression of GCH1.