Cirrhosis likely shares common pathophysiological pathways despite arising from a variety of liver diseases. A recent GWAS identified rs641738, a polymorphism in the MBOAT7 locus, as being associated with the development of alcoholic cirrhosis. Here we explore the role of this variant on liver inflammation and fibrosis in two cohorts of patients with chronic hepatitis C. In 2,051 patients, rs641738 associated with severe hepatic inflammation and increased risk of fibrosis, as well as fast fibrosis progression. At functional level, rs641738 associated with MBOAT7 transcript and protein levels in liver and blood, and with serum inflammatory, oxidative stress and macrophage activation markers. MBOAT7 was expressed in immune cell subsets, implying a role in hepatic inflammation. We conclude that the MBOAT7 rs641738 polymorphism is a novel risk variant for liver inflammation in hepatitis C, and thereby for liver fibrosis.

Adenoviruses use the short noncoding RNA transcript virusassociated (VA) RNA I to counteract two critical elements of the host cell defense system, innate cellular immunity and RNA interference, mediated by the double-stranded RNA-activated protein kinase (PKR) and Dicer/RNA-induced silencing complex, respectively. We progressively shortened the VA RNA I terminal stem to examine its necessity for inhibition of PKR. Each deletion, up to 15 bp into the terminal stem, resulted in a cumulative decrease in PKR inhibitory activity. Remarkably, however, despite significant apparent destabilization of the RNA structure, the final RNA mutant that lacked the entire terminal stem (TS⌬21 RNA) efficiently bound PKR and exhibited wild-type inhibitory activity. TS⌬21 RNA stability was strongly influenced by solution pH, indicating the involvement of a protonated base within the VA RNA I central domain tertiary structure. Gel filtration chromatography and isothermal titration calorimetry analysis indicated that wild-type VA RNA I and TS⌬21 RNA form similar 1:1 complexes with PKR but that the latter lacks secondary binding site(s) that might be provided by the terminal stem. Although TS⌬21 RNA bound PKR with wild-type K d , and overall change in free energy (⌬G), the thermodynamics of binding (⌬H and ⌬S) were significantly altered. These results demonstrate that the VA RNA I terminal stem is entirely dispensable for inhibition of PKR. Potentially, VA RNA I is therefore a truly bi-functional RNA; Dicer processing of the VA RNA I terminal stem saturates the RNA interference system while generating a "mini-VA RNA I " molecule that remains fully active against PKR.The interferon-induced double-stranded RNA (dsRNA) 4 -activated protein kinase (PKR) is a key component of the innate immune response that forms the first line of intracellular defense against viral infection (1, 2). PKR regulates translation initiation by phosphorylating the eukaryotic initiation factor 2 (eIF2) ␣-subunit at serine 51. The large increase in affinity of the phosphorylated form for its guanosine exchange factor (eIF2B) results in competitive inhibition and the reduction in available eIF2⅐GTP⅐Met-tRNA i Met ternary complex leads to a sharp reduction in both cellular and viral protein expression (3-5). Viruses devote large portions of their genomes to evading such host defenses and have evolved many different strategies to counter the PKR-mediated response (6). For example, Epstein-Barr virus and adenovirus produce large quantities of short noncoding RNA transcripts, EBER (7, 8) and VA RNAs, respectively (9, 10), that bind directly to PKR but inhibit rather than activate the kinase activity.All adenoviruses encode at least one VA RNA sequence (VA RNA I ) of ϳ160 nucleotides that is transcribed by the host RNA polymerase III and accumulates to very high concentrations in the late stages of infection (11, 12). Although VA RNA I sequences from different virus serotypes vary considerably, all can be drawn in a similar extended structure consisting of three major ...

dClass II membrane fusion proteins have been described in viruses in which the envelope proteins are derived from a precursor polyprotein containing two transmembrane glycoproteins arranged in tandem. Although the second protein, which carries the membrane fusion function, is in general well characterized, the companion protein, which is a protein chaperone for the folding of the fusion protein, is less well characterized for some viruses, like hepatitis C virus (HCV). To investigate the role of the class II companion glycoprotein E1 of HCV, we chose to target conserved cysteine residues in the protein, and we systematically mutated them in a full-length infectious HCV clone by reverse genetics. All the mutants were infectious, albeit with lower titers than the wild-type virus. The reduced infectivity was in part due to a decrease in viral assembly, as revealed by measurement of intracellular infectivity and by quantification of core protein released from cells transfected with mutant genomes. Analyses of mutated proteins did not show any major defect in folding. However, the mutations reduced virus stability, and they could also affect the density of infectious viral particles. Mutant viruses also showed a defect in cell-to-cell transmission. Finally, our data indicate that HCV glycoprotein E1 can also affect the fusion protein E2 by modulating its recognition by the cellular coreceptor CD81. Therefore, in the context of HCV, our data identify an additional function of a class II companion protein as a molecule that can control the binding capacity of the fusion protein.