Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus

Kamiyama, Reikou; Yoshimi, Ryusuke; Takeno, Mitsuhiro; Iribe, Yasuhiro; Tsukahara, Toshinori; Kishimoto, Daiga; Kunishita, Yosuke; Sugiyama, Yoshifumi; Tsuchida, Naomi; Nakano, Hajime; Tamura, Masahito; Asami, Yukiko; Kirino, Yohei; Ishigatsubo, Yoshiaki; Ozato, Keiko; Nakajima, Hitoshi

doi:10.1080/14397595.2018.1436028

Cited by 18 publications

(24 citation statements)

References 57 publications

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“…Anti-SS-A Ab is observed in sera of patients with autoimmune diseases such as SLE and Sjögren's syndrome, and TRIM21 is one of the autoantigens that bind to anti-SS-A Ab (57,58). We have shown that negative correlation between TRIM21 and type I IFNs expression, which is seen in PBMCs from healthy controls, disappeared in those from SLE patients, especially those with anti-TRIM21 Ab seropositivity (21). In this study, the differentiation from resting B cells to plasmablasts and Ab production were significantly increased in SLE patients with anti-TRIM21 Ab seropositivity as compared to those negative for anti-TRIM21 Ab.…”

Section: Discussionmentioning

confidence: 77%

“…It is conceivable that the high expression of IFN signature in SLE may be responsible for increased expression of TRIM21 as its suppression mechanism. Furthermore, our previous study showed that a negative correlation is observed between the expression of IFN signature mRNA and TRIM21 mRNA in healthy controls and SLE patients without anti-TRIM21 Ab who are considered to have normal function of TRIM21, but the correlation disappeared in SLE patients with anti-TRIM21 Ab (21). In this context, it was suggested that the function of TRIM21 is impaired by anti-TRIM21 Ab in patients with SLE.…”

Section: Aberrant B-cell Differentiation and Ab Production In Sle Patmentioning

confidence: 95%

“…Our previous study showed that TRIM21 mRNA and protein in PBMCs of patients with SLE were significantly higher than those of healthy controls and that the expression level of TRIM21 mRNA was well-correlated with disease activities of SLE (21). It is conceivable that the high expression of IFN signature in SLE may be responsible for increased expression of TRIM21 as its suppression mechanism.…”

Section: Aberrant B-cell Differentiation and Ab Production In Sle Patmentioning

confidence: 99%

“…It has been shown that TRIM21 is expressed at higher levels in peripheral blood mononuclear cells (PBMCs) in SLE patients as compared to healthy controls (21). Although the role of TRIM21 in SLE pathogenesis is still unknown, previous studies strongly suggest that TRIM21 can act as a suppressor for autoimmune and inflammatory response and its dysfunction can cause the pathological state of SLE.…”

Section: Introductionmentioning

confidence: 99%

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TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

et al. 2020

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TRIM21 is one of the autoantigens that reacts with an anti-SS-A antibody (Ab) present in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome. TRIM21 is thought to play a role in B-cell proliferation and apoptosis, among other activities. Here we examined a pathological role of TRIM21 in SLE. Trim21-deficient MRL/lpr mice were generated by backcrossing Trim21-deficient C57BL/6 mice to MRL/lpr mice. The levels of serum anti-dsDNA Ab and urine protein at 28 weeks of age were significantly higher in Trim21-deficient MRL/lpr mice as compared to wild-type MRL/lpr mice (p = 0.029 and 0.003, respectively). Resting B cells from Trim21-deficient mice showed significantly higher abilities to differentiate into plasmablasts and to produce Ab as compared with control mice. Due to the reduction of TRIM21-mediated ubiquitylation, IRF5 protein expression was increased in Trim21-deficient MRL/lpr mice (p = 0.021), which correlated with increased plasmablast generation and immunoglobulin production. B cells from SLE patients with anti-TRIM21 Ab seropositivity also showed a significantly higher ability to differentiate into plasmablasts as compared with those without anti-TRIM21 Ab or healthy controls. These results suggest that TRIM21 dysfunction contributes to SLE pathogenesis by promoting B-cell differentiation, for which anti-TRIM21 Ab may be partly responsible.

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Section: Discussionmentioning

confidence: 77%

Section: Aberrant B-cell Differentiation and Ab Production In Sle Patmentioning

confidence: 95%

Section: Aberrant B-cell Differentiation and Ab Production In Sle Patmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

et al. 2020

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“…The uncleaned apoptotic components which recognized by both the innate and the adaptive immune systems can trigger the pathogenesis of SLE. Therefore, the dysregulation of effective genes involved in the clearance of apoptotic components has a fundamental role in SLE [41][42][43][44][45]. Remarkably, we showed upregulation of MACROH2A1, SNRPD3, and Ro60 and downregulation of MACROH2A2, TRIM21…”

Section: Discussionmentioning

confidence: 62%

An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus

Maleknia

Salehi

Sharifi‐Zarchi

et al. 2020

Preprint

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Background: To perceive a comprehensive illustration of the systemic lupus erythematosus (SLE), as a complex and multifactorial disease, draw a biological challenge. Dealing with this challenge needs employing sophisticated bioinformatics algorithms to discover the unknown aspects. This study aimed to distinguish key molecular characteristics of SLE pathogenesis, which may serve as effective targets for therapeutic intervention. Methods: In the present study, six gene expression microarray datasets included SLE patients (n=220) and healthy controls (n=135) were collected. We integrated the datasets by cross-platform normalization. Subsequently, through BNrich method, the structures of Bayesian networks (BNs) were extracted from SLE, TCR and BCR signaling pathways and the parameters of BNs were estimated using integrated datasets. Finally, a meta-analysis was performed to distinguish the signaling pathways alterations in the SLE pathogenesis. Results: We identified the most dysregulated genes involved in the clearance mechanism (most inhibition in MACROH2A2 and H4C9, most activation in SNRPD3, MACROH2A1 and RO60). Augmented autoantigens presentation by MHCII (HLA-DQA1, HLA-DOB and HLA-DPB1) and CD80 and CD86 to CD28 biological functions were also observed. The increased expression of FCGR1A, C8G, C7 and C9 genes and decreasing biological functions in edges from C1R and C1S to C2 and from C1R to C4B, all involved in end-organ damage, were detected. On the other hand, many of subnetworks alterations of TCR and BCR reported in previous research (PI3K/AKT, MAPK, AP-1 transcription factor). Conclusions: Overall, the BNrich as a hybridized network construction method, which integrates intergenic relations inferred from signaling pathways and gene expression profiling, can be employed to study complex diseases. Here we applied BNrich and highlighted significant genes and intergenic relationships and systemic alterations in SLE, TCR and BCR signaling pathways.

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A Interacting Model: How TRIM21 Orchestrates with Proteins in Intracellular Immunity

Huang,

Gao,

et al. 2023

Small Methods

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Tripartite motif‐containing protein 21 (TRIM21), identified as both a cytosolic E3 ubiquitin ligase and FcR (Fragment crystallizable receptor), primarily interacts with proteins via its PRY/SPRY domains and promotes their proteasomal degradation to regulate intracellular immunity. But how TRIM21 involves in intracellular immunity still lacks systematical understanding. Herein, it is probed into the TRIM21‐related literature and raises an interacting model about how TRIM21 orchestrates proteins in cytosol. In this novel model, TRIM21 generally interacts with miscellaneous protein in intracellular immunity in two ways: For one, TRIM21 solely plays as an E3, ubiquitylating a glut of proteins that contain specific interferon‐regulatory factor, nuclear transcription factor kappaB, virus sensors and others, and involving inflammatory responses. For another, TRIM21 serves as both E3 and specific FcR that detects antibody‐complexes and facilitates antibody destroying target proteins. Correspondingly delineated as Fc‐independent signaling and Fc‐dependent signaling in this review, how TRIM21's interactions contribute to intracellular immunity, expecting to provide a systematical understanding of this important protein and invest enlightenment for further research on the pathogenesis of related diseases and its prospective application is elaborated.

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Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus

Abstract: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.

Cited by 18 publications

References 57 publications

TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus

A Interacting Model: How TRIM21 Orchestrates with Proteins in Intracellular Immunity

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