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SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA.

ABSTRACT: HBV infection initiates hepatitis B and promotes liver cirrhosis and hepatocellular carcinoma. IFN-α is commonly used in hepatitis B therapy, but how it inhibits HBV is not fully understood. We screened 285 human interferon-stimulated genes (ISGs) for anti-HBV activity using a cell-based assay, which revealed several anti-HBV ISGs. Among these ISGs, SAMD4A was the strongest suppressor of HBV replication. We found the binding site of SAMD4A in HBV RNA, which was a previously unidentified Smaug recognition region (SRE) sequence conserved in HBV variants. SAMD4A binds to the SRE site in viral RNA to trigger its degradation. The SAM domain in SAMD4A is critical for RNA binding and the C-terminal domain of SAMD4A is required for SAMD4A anti-HBV function. Human SAMD4B is a homolog of human SAMD4A but is not an ISG, and the murine genome encodes SAMD4. All these SAMD4 proteins suppressed HBV replication when overexpressed in vitro and in vivo. We also showed that knocking out the Samd4 gene in hepatocytes led to a higher level of HBV replication in mice and AAV-delivered SAMD4A expression reduced the virus titer in HBV-producing transgenic mice. In addition, a database analysis revealed a negative correlation between the levels of SAMD4A/B and HBV in patients. Our data suggest that SAMD4A is an important anti-HBV ISG for use in IFN therapy of hepatitis B and that the levels of SAMD4A/B expression are related to HBV sensitivity in humans.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7223975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The miR-99 family is one of the evolutionarily most ancient microRNA families, and it plays a critical role in developmental timing and the maintenance of tissue identity. Recent studies, including reports from our group, suggested that the miR-99 family regulates various physiological processes in adult tissues, such as dermal wound healing, and a number of disease processes, including cancer. By combining 5 independent genome-wide expression profiling experiments, we identified a panel of 266 unique transcripts that were down-regulated in epithelial cells transfected with miR-99 family members. A comprehensive bioinformatics analysis using 12 different sequence-based microRNA target prediction algorithms revealed that 81 out of these 266 down-regulated transcripts are potential direct targets for the miR-99 family. Confirmation experiments and functional analyses were performed to further assess 6 selected miR-99 target genes, including mammalian Target of rapamycin (mTOR), Homeobox A1 (HOXA1), CTD small phosphatase-like (CTDSPL), N-myristoyltransferase 1 (NMT1), Transmembrane protein 30A (TMEM30A), and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5). HOXA1 is a known proto-oncogene, and it also plays an important role in embryonic development. The direct targeting of the miR-99 family to two candidate binding sequences located in the HOXA1 mRNA was confirmed using a luciferase reporter gene assay and a ribonucleoprotein-immunoprecipitation (RIP-IP) assay. Ectopic transfection of miR-99 family reduced the expression of HOXA1, which, in consequence, down-regulated the expression of its downstream gene (i.e., Bcl-2) and led to reduced proliferation and cell migration, as well as enhanced apoptosis. In summary, we identified a number of high-confidence miR-99 family target genes, including proto-oncogene HOXA1, which may play an important role in regulating epithelial cell proliferation and migration during physiological disease processes, such as dermal wound healing and tumorigenesis.

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SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA.

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