Tripartite motif-containing 22 inhibits the activity of hepatitis B virus core promoter, which is dependent on nuclear-located RING domain

Abstract

Members of the tripartite motif (TRIM) family are a part of the innate immune system to counter intracellular pathogens. TRIM22 has been reported to possess antiretroviral activity. Here we report that TRIM22 is involved in antiviral immunity against hepatitis B virus (HBV). Our results showed that TRIM22, being a strongly induced gene by interferons in human hepatoma HepG2 cells, could inhibit HBV gene expression and replication in a cell culture system as well as in a mouse model system. Importantly, it was found that TRIM22 could inhibit the activity of HBV core promoter (CP) in a dose-dependent manner. However, TRIM22 lacking the C terminal SPRY domain lost this activity. Further study showed that the SPRY domain deletion mutant was localized exclusively to the cytoplasm of HepG2 cells. In contrast, the wild-type TRIM22 was localized to the nucleus, as expected for a transcriptional suppressor. Interestingly, although RING domain mutants of TRIM22 were localized to the nucleus, they could not inhibit HBV CP activity, indicating that TRIM22-mediated anti-HBV activity was dependent on the nuclear-located RING domain. W ith over 300 million carriers, hepatitis B virus (HBV) infection remains a major public health problem worldwide. 1 Classified in the Hepadnaviridae family, HBV is a small, enveloped DNA virus with a genome size of 3.2 kb. HBV replicates its partially double-stranded DNA genome within core particles by reverse transcription of encapsulated 3.5-kb pregenomic RNA (pgRNA), and thus is related to retroviruses. 2 The core promoter (CP) is responsible for the synthesis of pgRNA, and therefore the regulation of this promoter is important in the viral life cycle. It is well established that resolution of HBV infection is critically dependent on adaptive immunity, especially on HBVspecific cytotoxic T lymphocytes response. However, many studies also indicate that an innate immune response is crucial for early clearance of HBV infection. 3 For example, activation of Toll-like receptor signaling can inhibit HBV replication in vivo, and overexpression of an innate antiviral molecule, APOBEC3G, has also been shown to interfere with HBV replication efficiently. 4,5 Recent studies show that many members of the tripartite motif (TRIM) superfamily are expressed in response to interferons (IFNs) and display antiviral properties, targeting retroviruses in particular. 6,7 TRIM5␣, TRIM19, TRIM22, and TRIM28 were all demonstrated to play important roles in antiretroviral activities. [8][9][10][11][12] It has been speculated that the TRIM proteins may represent a new and widespread class of antiviral molecules involved in innate immunity. 6,7 The TRIM family is characterized by a combination of RING, B-Box, and coiled-coil domains, followed by one of several C-terminal domains. 13 To date, nearly 70 TRIM family members have been identified, yet the most intensively studied TRIM protein may be

Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A

“…Because liver biopsy samples were not available, it is unclear whether TRIM22 was also induced in hepatocytes. Previous research 13 has demonstrated that TRIM22 is upregulated in liver cell lines, consistent with its up-regulation in PBMCs. In the present study, upregulation of TRIM22 was also observed in Huh-7 cells after IFNa treatment.…”

“…19,24,25 Gao and colleagues observed that TRIM22 was mainly localized in the nucleus of HepG2 cells when it suppresses HBV survival. 13 The discrepancy in localization compared to our present study may be due to the different cell lines we used (Huh-7 cell lines). The mechanism by which TRIM22 suppresses HCV replication is of substantial interest.…”

“…10,11 For example, TRIM22 inhibits influenza by targeting its nucleoprotein, but also inhibits the activity of the HBV core promoter not through ubiquitination. 13 We previously determined that TRIM22 is highly upregulated in peripheral blood mononuclear cell (PBMC) samples from HCV patients treated with IFNa, as well as in Huh-7 cells treated with IFNa. 13 The function of TRIM22 was further verified by examining its effects on the HCV Huh-7-Con-1 replicon system or JFH1 virus.…”

“…13 We previously determined that TRIM22 is highly upregulated in peripheral blood mononuclear cell (PBMC) samples from HCV patients treated with IFNa, as well as in Huh-7 cells treated with IFNa. 13 The function of TRIM22 was further verified by examining its effects on the HCV Huh-7-Con-1 replicon system or JFH1 virus. Here, the mechanism of TRIM22 is explored.…”

Genome of the Chinese tree shrew

“…TRIM5, one of the host restriction factors blocking retroviral replication 44 , is located in a gene cluster in human with three other closely related TRIM genes, including TRIM6, TRIM34 and TRIM22. Genes in this cluster have also been suggested to inhibit the activity of HBV 45 . In the tree shrew, this gene cluster displays a dynamic evolutionary episode (Fig.…”