Reddi Tejaswini S, Merkl Philipp E, Lim So-Yon, Letvin Norman L, Knipe David M
Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Pathog. 2021 Feb 1;17(2):e1009281. doi: 10.1371/journal.ppat.1009281. eCollection 2021 Feb.
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-1 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.
内在抗性是抵御病毒感染的关键防线，三方环相互作用基序（TRIM）蛋白家族成员是该系统中的主要参与者，如细胞质中的TRIM5α或细胞核中的早幼粒细胞白血病（PML/TRIM19）蛋白。先前关于另一种TRIM蛋白TRIM22抗病毒功能的报道强调了其作为针对RNA病毒的I型和II型干扰素刺激基因的固有免疫作用。本研究表明，TRIM22对DNA病毒具有额外的固有作用。在此，我们报道TRIM22是单纯疱疹病毒-1（HSV-1）的一种新型限制因子，通过增加组蛋白占据率和异染色质来限制ICP0缺失病毒的复制，从而降低病毒立即早期基因的表达。病毒相应的野生型通过一种独立于ICP0介导的降解机制逃避TRIM22特异性限制。我们还证明TRIM22抑制其他DNA病毒，包括β-和γ-疱疹病毒的代表性成员。TRIM22中的等位基因变体表现出不同程度的抗疱疹病毒活性；因此，TRIM22的基因变异性可能导致人类对HSV-1感染的易感性不同。总的来说，这些结果表明TRIM22是一种新型限制因子，并扩展了在受感染细胞核中发挥作用以对抗DNA病毒感染的限制因子列表。
