Enhancement of Th1/Th17 inflammation by TRIM21 in Behçet’s disease

Ahn, Young Soo; Hwang, Jin Soo; Zheng, Zhenlong; Bang, Dongsik; Kim, Doyoung

doi:10.1038/s41598-017-03251-5

Cited by 27 publications

(27 citation statements)

References 44 publications

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“…A recent study reveals that TRIM21 expression is increased in monocytes isolated from Behçet’s disease (BD, an autoimmune disease) patients. Monocytes from BD patients facilitate differentiation of Th1 and Th17 when cultured with naïve T cells, whereas knockdown of TRIM21 inhibits Th1 and Th17 differentiation ( 161 ), highlighting the synergistic effects of TRIM21 in innate and adaptive immunity.…”

Section: Trims Regulate T Cell Functionsmentioning

confidence: 99%

To TRIM the Immunity: From Innate to Adaptive Immunity

Yang

Zhang

et al. 2020

Front. Immunol.

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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.

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Section: Trims Regulate T Cell Functionsmentioning

confidence: 99%

To TRIM the Immunity: From Innate to Adaptive Immunity

Yang

Zhang

et al. 2020

Front. Immunol.

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“…TRIM21 enhances IL-2 production in human immortalized T cells in response to CD28 stimulation 14 . It is also involved in Th1/Th17 differentiation through secretion of proinflammatory cytokines 15 . Furthermore, T-cell proliferation and IL6 production have been found to be regulated by TRIM21 16 .…”

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confidence: 99%

Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation

Guha

Nag

Ray

2020

Sci Rep

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The E3 ubiquitin ligase TRIM21 plays a crucial role as a negative regulator of innate immune responses. Recent evidence has also indicated the involvement of TRIM21 in the genotoxic stress response and suppressing tumorigenesis. Our previous work has demonstrated a new function of TRIM21 in inhibiting p53 protein synthesis by degrading the RNA-binding protein HuR in response to UV radiation. This suggested a pro-oncogenic role of TRIM21. In this study, we have shown that TRIM21 enhances the proliferation of MCF7 breast carcinoma cells and counteracts the decrease in cell proliferation and colony formation caused by UV-induced DNA damage. Further, this pro-oncogenic role of TRIM21 in response to DNA damage is mediated by its degradation of HuR. Conversely, we found that HuR binds to a U-rich element in the 3′UTR of TRIM21 mRNA and activates its translation, thereby constituting a negative feedback loop. We found that dihydrotanshinone-I (DHTS-I), a plantderived product which prevents HuR binding to specific RNAs, prevented HuR-mediated upregulation of TRIM21, while increasing the HuR-mediated upregulation of p53. Together, these findings demonstrate a negative feedback regulation between TRIM21 and HuR, which may play an important role in regulating the level of p53 in the genotoxic stress response. TRIM (Tripartite motif) family proteins are ubiquitously found in all metazoans and are recognized for conserved biological functions, such as control of cell proliferation and differentiation. However, with the appearance of complex immune systems in jawed vertebrates, some of these have evolved to directly regulate antiviral action and cytokine production. TRIM family proteins are primarily recognized as post-translational modifiers. Nevertheless, some of the members of this family are implicated in RNA metabolism. These TRIM proteins are specifically localized in the cytoplasmic processing bodies. Furthermore, about half of all the TRIM family proteins are involved in autophagy. Most of these are also involved in the formation of TRIMosomes which are considered to facilitate autophagic engulfment and subsequent lysosomal degradation 1. E3 ubiquitin ligase TRIM21 is a 52 kDa protein belonging to the TRIM family. Similar to many other TRIM family proteins, TRIM21 has a characteristic N-terminal RING domain, B-box domain, coiled-coil domain (collectively called RBCC). The RING domain is implicated in E3 ubiquitin ligase activity, whereas the B-box domain has been shown to be a negative regulator of RING domain. Recently, the phosphorylation of serine-80 (S80) or phosphomimetic serine-80 to glutamate (S80E) mutation in TRIM21 has been found to release the inhibition of B-box domain 2,3. The coiled-coil domain is utilized in homo-dimerization of TRIM21 which ensures binding with the substrate in a stoichiometry of 2:1 2. TRIM21 has also C-terminal PRYSPRY domain which is required for target protein recognition. Structural analysis of PRYSPRY domain of TRIM21 has demonstrated its diverse functions. Isothermal titration ca...

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“…Among TRIM family members, TRIM21 acts not only as an E3 ubiquitin ligase on different target proteins, but also as a substrate in auto-ubiquitination, both leading to protein degradation [56,57,58]. In addition, TRIM21 is involved in cancer [59,60], inflammation [61,62,63,64], intracellular immunity, and autoimmunity [47,65,66,67]. Here, we validated the protein screen data for TRIM21, using two-way co-immunoprecipitation analysis of endoglin and TRIM21 in HUVECs and co-transfected CHO-K1 cells (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

Gallardo-Vara

Ruíz-Llorente

Casado‐Vela

et al. 2019

Cells

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Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.

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Enhancement of Th1/Th17 inflammation by TRIM21 in Behçet’s disease

Cited by 27 publications

References 44 publications

To TRIM the Immunity: From Innate to Adaptive Immunity

To TRIM the Immunity: From Innate to Adaptive Immunity

Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation

Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners

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