Fig 1.
The general structure of TRIM proteins is represented at the top of the figure, with the functions associated to each domain. Only the TRIM proteins mentioned in this review are listed in this figure. Ub: ubiquitin; SUMO: Small Ubiquitin-like Modifier; COS: C-terminal subgroup One Signature; FN3: fibronectin type III domain; AR: acid-rich region; SPRY: SPIa and the ryanodine receptor domain; PRY: SPRY-associated domain; PHD: plant homeodomain; BROMO: bromodomain; FIL: filamin-type IG domain; NHL: NHL repeats; MATH: meprin and tumor necrosis factor receptor–associated factor homology domain; ARF: ADP-ribosylation factor family domain; TM: transmembrane region; UC: unclassified. Created in BioRender. Lucifora, J. (2025) https://BioRender.com/j55c338.
Fig 2.
TRIM proteins positively regulate innate immune signaling pathways.
Upon recognition of viral DNAs or RNAs, pattern-recognition receptors (PRRs) such as TLR3, cGas/STING and RLRs (RIG-I and MDA5) are activated by TRIM proteins [12,15–20,26,28]. Except for TLR3, this positive regulation is dependent on polyubiquitination or SUMOylation catalyzed by TRIM proteins. TRIM proteins actions on immune signaling pathways result in the promotion of type I interferon production, which in turn activates the expression of many TRIM proteins, through the JAK/STAT signaling pathway. TRIM21 itself detects intracellular opsonized viruses and initiates the NF-κB pathway [25,26]. Created in BioRender. Lucifora, J. (2025) https://BioRender.com/d11y722.
Table 1.
TRIM proteins upregulated in response to interferon stimulation. Systematic analysis of TRIM genes whose expression is induced by type I and type II interferons in human primary lymphocytes and monocyte-derived macrophages. Data from [29].
Fig 3.
TRIM proteins directly antagonize viruses.
In general, TRIM proteins ubiquitinate viral proteins, leading to their proteasomal degradation. TRIM2 inhibits New World Arenavirus (NWA) entry [37]. TRIM32 impairs the uncoating of Venezuelan equine encephalitis virus (VEEV) [38]. TRIM5α forms a shield around HIV capsid [39] and HIV expression is impaired by TRIM22 [48]. Other TRIM proteins degrade transcription factors, such as TRIM21 [40], TRIM26 [44] and TRIM65 [41] which limit the expression of Hepatitis B virus (HBV) genome. TRIM23 [45] and TRIM22 [49] inhibit the expression of Herpes simplex virus (HSV), respectively by promoting the degradation of ICP0 and chromatin compaction. TRIM72 targets the Matrix (M) protein of Rabies virus (RABV) for degradation, preventing virus assembly [47]. Created in BioRender. Lucifora, J. (2025) https://BioRender.com/q00o031.
Fig 4.
TRIM proteins initiate the autophagic degradation of certain viruses.
TRIM5α binds to HIV capsid and catalyzes the formation of polyubiquitin chains leading to the recruitment of p62 and LC3, both of which are involved in autophagosome formation [39]. The Herpes simplex virus (HSV) infection triggers TRIM23 auto-ubiquitination which activates its GTPase activity [54]. The GTP-GDP cycle promotes TBK1 auto-phosphorylation, which in turn leads to the association with p62. The autophagosome then fuses with a lysosome and the combined action of lysosomal enzymes and low pH degrades viral components. Created in BioRender. Lucifora, J. (2025) https://BioRender.com/r82i202.
Fig 5.
Examples of viruses escaping the restriction mediated by TRIM proteins.
Left side: Viruses inhibit the antiviral action of TRIMs. NS1 protein of Influenza A virus (IAV) impairs the activation of RIG-I by TRIM25 [56]. TRIM23 is antagonized by HSV proteins γ134.5 [45] and Us11 [63], removing the restriction on HSV expression and blocking autophagy initiation. IE1 protein of human cytomegalovirus (HMCV) impedes the SUMOylation of TRIM19, leading to nuclear body (NB) disruption and release of viral proteins [58]. Right side: Viruses take advantages of TRIM-mediated modifications. Polyubiquitination of the Zika virus (ZIKV) envelope protein promotes its interaction with the TIM-1 receptor [64]. TRIM6-mediated modification of VP35 stabilizes L polymerase on the Ebola virus (EBOV) genome [65]. In addition, TRIM6 facilitates the association of the nucleoprotein (NP) of SARS-CoV-2 with the viral genome [67]. TRIM44 promotes the initiation of autophagy, which facilitates RABV replication [68]. Human papillomavirus (HPV) E7 protein enables polyubiquitination of IFI16 by TRIM21, inhibiting inflammasome assembly and pyroptosis [70]. Created in BioRender. Lucifora, J. (2025) https://BioRender.com/q85j502.