The antiviral activities of TRIM proteins

Abstract

Tripartite motif (TRIM) proteins are a highly versatile family of host-cell factors that play an integral role in the mammalian defense against pathogens. TRIM proteins regulate either transcription-dependent antiviral responses such as pro-inflammatory cytokine induction, or they modulate other important cell-intrinsic defense pathways like autophagy. Additionally, TRIM proteins exert direct antiviral activity whereby they antagonize specific viral components through diverse mechanisms. Here, we summarize the latest discoveries on the molecular mechanisms of antiviral TRIM proteins and also discuss current and future trends in this fast-evolving field.

Figure 1.. TRIM family protein domain structure and groups

TRIM proteins are characterized by a common RBCC motif. The RBCC motif is comprised of a RING domain conferring E3 ligase activity, one or two BBoxes of mostly unknown function, and a coiled-coil domain that is important for multimerization. The unique C-terminal domains of TRIM proteins have diverse functions including protein-protein interaction, enzymatic activity (e.g. ARF GTPase activity), membrane anchoring, and RNA binding. According to their C-terminal domains, TRIM proteins are classified into 11 major groups. Of note, several TRIM proteins (also called ‘TRIM-like proteins’) that lack the RING or additional domains of the RBCC motif are categorized as ‘unclassified’; these TRIMs are not illustrated for simplicity.

Figure 2.. Major antiviral functions of TRIM proteins

TRIM proteins employ at least three major antiviral mechanisms: (i) modulation of autophagy, a cell-intrinsic autodigestive pathway that limits the replication of certain viruses; (ii) regulation of cytokine induction and cytokine-mediated antiviral innate immune responses; and (iii) direct targeting of viral components, which triggers their degradation or inhibits their functions in key steps of the viral lifecycle. Of note, while some TRIM proteins utilize one of the three antiviral mechanisms, several TRIMs exert immunomodulatory functions and also directly antagonize viral pathogens. Exemplary TRIM proteins involved in specific steps of the antiviral response are indicated. RBCC, RING-BBox-coiled-coil motif.