TRIM22 IS A NOVEL RESTRICTION FACTOR OF HERPESVIRUSES

Abstract

The host response to the family of nuclear replicating DNA viruses or the herpesviruses includes the intrinsic, innate and adaptive arms of the immune system. Intrinsic resistance is a constitutively active line of defense against virus infections and members of the Tripartite Motif (TRIM) superfamily of proteins; such as TRIM5 and TRIM19/PML in nuclear domain 10 (ND10) bodies are important restriction factors in this system. Nuclear intrinsic restriction against the prototypical DNA virus, herpes simplex virus 1 (HSV-1) includes interferon-inducible protein 16 (IFI16) and ND10 bodies. However, the viral E3 ubiquitin ligase, ICP0, encoded by wild-type HSV-1, targets these intrinsic immune proteins for degradation. Previous reports on the anti-viral function of TRIM22, the human paralog of the prototypical TRIM5α protein, emphasized its role as a gene of the innate immune system, particularly its expression as a Type I and Type II interferon-stimulated gene and its antiviral function against retroviruses. This study shows that TRIM22 has an additional intrinsic immune role against DNA viruses, using the herpesviruses as an example of a family of DNA viruses. We report that TRIM22 is a novel restriction factor of HSV-1 and limits HSV-1 ICP0-null virus replication. The TRIM22-mediated restriction of HSV-1 occurs after nuclear entry but prior to viral immediate-early gene transcription, by promoting histone occupancy and heterochromatinization to reduce immediate-early viral gene expression. The ICP0-rescued virus evades the TRIM22-specific restriction by a mechanism independent of TRIM22 degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of the β- and γ- herpesviruses. These results collectively show that TRIM22 acts in the nucleus, and provide evidence that TRIM22 restricts HSV gene expression by promoting histone occupancy on the viral genes. Furthermore, we identified seven haplotypic variants of TRIM22 and propose that amino acid substitutions in the linker L2 domain and the coiled-coil domain of TRIM22 alter the magnitude of its restriction against the herpesviruses. Together, these results argue for the importance of the TRIM22 gene as a restriction factor against herpesviruses and offer a novel avenue for further investigation on the role of TRIM genes in host genetic variation in herpesviral susceptibility.