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. 2020 Oct 8:11:02157.
doi: 10.3389/fimmu.2020.02157. eCollection 2020.

To TRIM the Immunity: From Innate to Adaptive Immunity

Wenyong Yang  1 , Zhiwen Gu  1 , Huiyuan Zhang  1 , Hongbo Hu  1
Affiliations

To TRIM the Immunity: From Innate to Adaptive Immunity

Wenyong Yang et al. Front Immunol. .

Abstract

The tripartite motif (TRIM) proteins have been intensively studied as essential modulators in various biological processes, especially in regulating a wide range of signaling pathways involved in immune responses. Most TRIM proteins have E3 ubiquitin ligase activity, mediating polyubiquitination of target proteins. Emerging evidence demonstrates that TRIM proteins play important roles in innate immunity by regulating pattern recognition receptors, vital adaptor proteins, kinases, and transcription factors in innate immune signaling pathways. Additionally, the critical roles of TRIM proteins in adaptive immunity, especially in T cell development and activation, are increasingly appreciated. In this review, we aim to summarize the studies on TRIMs in both innate and adaptive immunity, focusing on their E3 ubiquitin ligase functions in pattern recognition receptor signaling pathways and T cell functions, shedding light on the developing new strategies for modulating innate and adaptive immune responses against invading pathogens and avoiding autoimmunity.

Keywords: adaptive immunity; innate immunity; signal; tripartite motif; ubiquitination.

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Figures

Figure 1
Figure 1
Structures of TRIM protein. TRIM proteins are generally divided into 11 subgroups depending on their variable C-terminal domains, including C-terminal subgroup one signature (COS) domain, fibronectin type 3 (FN3) domain, SPIa and the ryanodine receptor (SPRY) domain, SPRY-associated domain (PRY), plant homeodomain (PHD), bromodomain (BR), filamin domain, NHL repeats (NHL) domain, meprin and tumor necrosis factor receptor–associated factor homology (MATH) domain, ADP-ribosylation factor (ARF) domain, and transmembrane (TM) domain. The N-terminal domains are conserved among TRIM proteins, containing a RING domain, a B-box 1 (B1) and/or a B-box 2 (B2) domain, and a CC domain. TRIM-like proteins lacking typical domain(s) are indicated in brackets.
Figure 2
Figure 2
Schematic diagram of TRIM-mediated regulation of the TLR signaling pathway. The TLR signaling is divided into two distinct pathways: the MyD88- and TRIF-dependent pathways. In the MyD88-dependent pathway, activated MyD88 recruits and further activates the IRAK1 kinase complex, which then recruits TRAF6, an E3 ligase that undergoes auto-ubiquitination and mediates the recruitment and auto-phosphorylation of TAK1 complex. Activated TAK1 promotes IκBα phosphorylation, which leads to the degradation of IκBα, and releases NF-κB p50/p65 subunits into nuclear, promote the production of a subset of proinflammatory cytokines. In the TRIF-dependent pathway, activated TRIF recruits TRAF3, an E3 ligase that mediates the activation of TBK1, leading to the phosphorylation and dimerization of IRF3 to promote the production of IFN-I. This figure overviews the known TRIM proteins that regulate the TLR signaling pathway, in which the TRIMs promoting TLR signaling are indicated in green, whereas those suppressing TLR signaling are indicated in red.
Figure 3
Figure 3
TRIMs regulate RLRs and cytosolic DNA-sensing receptor pathways. The RLRs and cytosolic DNA-sensing receptor pathways regulated by TRIM proteins. RLRs are crucial cytoplasmic PRRs that are responsible for recognition of RNA virus infections, whereas cytosolic DNA-sensing receptors recognize host and microbial DNA in the cytosolic. They both finally activate NF-κB and IRFs to induce the production of proinflammatory cytokines and type I IFNs. This figure illustrates TRIM proteins that modulate RLRs and cytosolic DNA-sensing receptor signaling pathways, and the details of the modulation mechanisms are described in the text. TRIMs promoting RLRs and cytosolic DNA-sensing signaling pathways are indicated in green, whereas these exerting the opposite functions are indicated in red.
Figure 4
Figure 4
The function of TRIMs in NLRs and inflammasome pathways. The NLR and inflammasome pathways are intracellular PRRs sensing PAMPs or DAMPs associated with cell stress. Activated inflammasome activates pro-caspase-1 and cleaves IL-1β and IL-18 precursors into the functional forms, which are subsequently secreted out of the cell to induce inflammatory responses. This figure illustrates TRIM proteins regulating NLRs and inflammasome pathways. TRIMs promoting NLRs and inflammasome pathways are indicated in green, whereas these exerting the opposite functions are indicated in red.
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