The tripartite motif (TRIM) family of proteins is an evolutionarily ancient group of proteins with homologues identified in both invertebrate and vertebrate species. Human TRIM22 is one such protein that has a dynamic evolutionary history that includes gene expansion, gene loss, and strong signatures of positive selection. To date, TRIM22 has been shown to restrict the replication of a number of viruses, including encephalomyocarditis virus (EMCV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1). In addition, TRIM22 has also been implicated in cellular differentiation and proliferation and may play a role in certain cancers and autoimmune diseases. This comprehensive paper summarizes our current understanding of TRIM22 structure and function. 1. Introduction The TRIM gene family encodes a diverse group of proteins that are involved in many biological and antiviral processes. There are currently 100 known TRIM genes in the human genome and many of these genes are upregulated by multiple, distinct stimuli [1–3]. Historically, TRIM genes have been researched mainly for their antiviral properties; however this paradigm is changing. Two recent reports discussing the role of TRIM genes in autoimmunity and cancer highlight the importance of the TRIM family in the development of nonviral diseases [4, 5]. Many TRIM genes also have a dynamic evolutionary history and the TRIM family has been shown to undergo extensive gene duplication in both primates and teleost fish [1, 6]. In addition, several TRIM genes have experienced strong positive selection in primates [7]. Although the forces behind TRIM evolution remain unclear, it is possible that the TRIM family has evolved and continues to evolve, in response to new viral pathogens or endogenous danger signals. This paper provides an overview of the TRIM22 gene and summarizes its structure, evolution, expression, and antiviral activities. 2. Structure TRIM proteins typically contain a conserved RBCC motif, which consists of an amino-terminal RING domain, one or two B-box domains, and a predicted coiled-coil region. Approximately 60% of TRIM proteins, including TRIM22, also contain a carboxyl-terminal domain B30.2 domain (Figure 1) [8, 9]. The RING domain of TRIM22 has homology with E3 ligases and has been shown to possess E3 ubiquitin ligase activity [9, 10]. The catalytic cysteine residues Cys15 and Cys18 are essential for this activity and mediate the transfer of ubiquitin to target proteins (Figure 1) [11, 12]. TRIM22 can also modify itself with ubiquitin which leads to proteasomal
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