Ro52/SSA sensitizes cells to death receptor‐induced apoptosis by down‐regulating c‐FLIP(L)

Zhang, Jing; Fang, Lei; Zhu, Xuguo; Qiao, Yiting; Yu, Min; Wang, Lu; Chen, Yuan; Wu, Yin; Zhang, Hua

doi:10.1042/cbi20110322

Cited by 13 publications

(14 citation statements)

References 22 publications

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“…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. In combination with previously reported in vitro data that TRIM21 has a suppressive role in human B-cell proliferation (19,20,59), these results strongly suggest that the disruption of TRIM21 fu0nction can be caused partly by anti-TRIM21 Ab in patients with SLE. Consistent with this hypothesis, B-cell differentiation and Ab production were increased in the Trim21 −/− MRL/lpr mice as compared with the Trim21 +/+ MRL/lpr mice in our experiments.…”

Section: Discussionsupporting

confidence: 82%

“…There could be the possibility that the rate of plasmablasts was influenced by cell life-span because some previous reports showed that TRIM21 acts on apoptosis-related molecules such as BCL-2 and c-FLIP (19,20). However, there was no significant difference in the survival of B cells at 24 h after stimulation between Trim21 +/+ MRL/lpr and Trim21 −/− MRL/lpr mice (Supplemental Figure 1C).…”

Section: Trim21 Deficiency Promotes Aberrant B-cell Differentiation Amentioning

confidence: 93%

“…TRIM21 ubiquitylates IFN regulatory factors (IRFs) via its E3 ubiquitin ligase activity on the RING-finger domain and regulates the production of type I IFN and IL-12p40 (13)(14)(15)(16)(17)(18). It has been reported that the TRIM21 overexpression in a B-cell line leads to reduced growth and increased apoptosis after activation (19,20).…”

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: Discussionsupporting

confidence: 82%

Section: Trim21 Deficiency Promotes Aberrant B-cell Differentiation Amentioning

confidence: 93%

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TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

et al. 2020

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“…Thirdly, we have previously demonstrated that increased expression of TRIM21 leads to decreased proliferative capacity in a mouse B‐cell lymphoma cell line . Finally, TRIM21 is an E3 ligase involved in ubiquitination, and there are emerging data to suggest that it regulates multiple proteins important in the cell cycle and apoptosis, such as BCL2 and interferon regulatory factor (IRF)‐8 as well as FADD and c‐FLIP . Based on these observations, we investigated the role of TRIM21 in lymphoma and its potential as a prognostic biomarker in patients with DLBCL.…”

Section: Introductionmentioning

confidence: 99%

Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B‐cell lymphoma patients with and without rheumatic disease

et al. 2015

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Objective TRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B‐cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. Materials and methods TRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)‐like regimen, 76 CHOP‐treated and 196 rituximab‐CHOP‐treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with 3H‐thymidine incorporation and propidium iodine staining. Results TRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression‐free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes in vitro. Conclusions We show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

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“…Ro52/SSA can negatively regulate the long form of FLIP (FLIP(L)) in vitro , as overexpression of Ro52/SSA reduces FLIP(L) and knockdown of Ro52/SSA results in the accumulation of FLIP(L) [129]. Peripheral blood B cells from patients with SLE present with significantly higher expression of FLIP, which correlates with SLE severity, as patients with active SLE show higher FLIP levels that patients with inactive SLE [130].…”

Section: Programmed Cell Death Pathways In Dendritic Cells and Macmentioning

confidence: 99%

The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

Tsai

Perlman

Cuda

2017

Clinical Immunology

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Systemic lupus erythematosus (SLE) is a chronic multi-factorial autoimmune disease initiated by genetic and environmental factors, which in combination trigger disease onset in susceptible individuals. Damage to the kidney as a consequence of lupus nephritis (LN) is one of the most prevalent and severe outcomes, as LN affects up to 60% of SLE patients and accounts for much of SLE-associated morbidity and mortality. As remarkable strides have been made in unlocking new inflammatory mechanisms associated with signaling molecules of programmed cell death pathways, this review explores the available evidence implicating the action of these pathways specifically within dendritic cells and macrophages in the control of kidney disease. Although advancements into the underlying mechanisms responsible for inducing cell death inflammatory pathways have been made, there still exist areas of unmet need. By understanding the molecular mechanisms by which dendritic cells and macrophages contribute to LN pathogenesis, we can improve their viability as potential therapeutic targets to promote remission.

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Ro52/SSA sensitizes cells to death receptor‐induced apoptosis by down‐regulating c‐FLIP(L)

Cited by 13 publications

References 22 publications

TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis

Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B‐cell lymphoma patients with and without rheumatic disease

The contribution of the programmed cell death machinery in innate immune cells to lupus nephritis

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