Tripartite Motif 22 (TRIM22) protein restricts herpes simplex virus 1 by epigenetic silencing of viral immediate-early genes

Abstract

Intrinsic resistance is a crucial line of defense against virus infections, and members of the Tripartite Ring Interaction Motif (TRIM) family of proteins are major players in this system, such as cytoplasmic TRIM5α or nuclear promyelocytic leukemia (PML/TRIM19) protein. Previous reports on the antiviral function of another TRIM protein, TRIM22, emphasized its innate immune role as a Type I and Type II interferon-stimulated gene against RNA viruses. This study shows that TRIM22 has an additional intrinsic role against DNA viruses. Here, we report that TRIM22 is a novel restriction factor of HSV-1 and limits ICP0-null virus replication by increasing histone occupancy and heterochromatin, thereby reducing immediate-early viral gene expression. The corresponding wild-type equivalent of the virus evades the TRIM22-specific restriction by a mechanism independent of ICP0-mediated degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of the β- and γ- herpesviruses. Allelic variants in TRIM22 showed different degrees of anti-herpesviral activity; thus, TRIM22 genetic variability may contribute to the varying susceptibility to HSV infection in humans. Collectively, these results argue that TRIM22 is a novel restriction factor and expand the list of restriction factors functioning in the infected cell nucleus to counter DNA virus infection.

TRIM22. A Multitasking Antiviral Factor

“…The mechanisms of TRIM22 antiviral restriction may depend on the RING domain that has E3 ubiquitin ligase activity, as demonstrated for IAV [86], HBV [31] and EMCV [87]. However, other mechanisms that involve the CC domain or the B30.2 domain, as for HIV-1 [20] and HSV-1, participate in its antiviral activity [114].…”

“…All three subfamilies encompass viruses that are pathogenic for humans, and that can also cause severe disease [121]. Among the alpha-herpesviruses, it has recently been demonstrated that herpes simplex virus I (HSV-1) is inhibited by TRIM22 [114]. The mechanism of inhibition relies on TRIM22 activity to silence viral DNA encoding immediate-early viral genes by promoting chromatin compaction.…”

“…Previous studies have provided evidence that the latent membrane protein 1 (LMP1) of EBV induces an antiviral state by upregulating ISGs including TRIM22 [112]. More recently, TRIM22 was shown to reduce the efficiency of EBV infection [114]. Among gamma-herpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV), also known as HHV8, has also been shown to induce TRIM22.…”

Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes

“…Thus, IFI16 serves as an intrinsic resistance factor at basal levels that is induced as an innate response to block wildtype viral replication. Another gene product that we observed as elevated in the surrounding uninfected cells is TRIM22, which we recently showed to be a restriction factor for HSV-1 infection ( 51 ). Together, our results demonstrate that adaptive immune cells can instruct the innate immune responses in tissue microenvironments to mount mechanisms that restrict viral replication, thus providing evidence of a new feedback loop connecting adaptive and innate immune mechanisms.…”

Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses

“…Similarly, TRIM22 has been identified as an intrinsic host cell factor limiting HSV replication via the viral genome’s heterochromatinization. ICP0 has been shown to disrupt this intrinsic defense in a mechanism independent of ICP0’s ubiquitin ligase activity [ 73 ]. Additionally, ICP0 interacts with promyelocytic leukemia protein (PML) and facilitate its SUMO-independent degradation as a viral countermeasure to circumvent PML-mediated antiviral restrictions [ 74 ].…”