E3 ubiquitin ligases Pellinos as regulators of pattern recognition receptor signaling and immune responses

Medvedev, Andrei E.; Murphy, Michael; Zhou, Hao; Li, Xiaoxia

doi:10.1111/imr.12298

Cited by 52 publications

(53 citation statements)

References 114 publications

(203 reference statements)

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“…Instead, enhanced TLR4‐ or TLR7‐driven IRAK4‐mediated activation of MAPKs, NF‐κB and increased TNF‐α and CCL5 gene expression in macrophages from mice with lupus correlated with lower expression of Tollip and IRAK‐M, negative regulators of TLR signaling . In contrast, no significant changes in the mRNA levels of Pellino‐1 (positive) or Pellino‐3 (negative) regulators were observed, indicating the selective effect of lupus on expression of TLR regulators. IRAK‐M acts by preventing dissociation of IRAK1 from MyD88 or via inducing other negative regulators, such as A20, SHIP‐1, inhibitor of NF‐κB‐α , whereas Tollip suppresses IRAK1 activation .…”

Section: Discussionmentioning

confidence: 89%

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Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

et al. 2017

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Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumonia, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus. Lupus development in BXSB mice expressing the Y chromosome autoimmunity accelerator (Yaa) increased basal and Toll-like receptor (TLR) 4/7-induced phosphorylation of mitogen-activated protein kinases, p65 nuclear factor-κB (NF-κB), enhanced tumor necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL) 5 gene expression in splenic macrophages, but decreased levels of Toll-interacting protein and IRAK-M, without affecting IRAK4 or IRAK1 expression. Mice harboring kinase-inactive IRAK4 on the lupus-prone Yaa background manifested blunted TLR signaling in macrophages and reduced glomerulonephritis, splenomegaly, serum anti-nuclear antibodies, numbers of splenic macrophages, total and TNF-α+ dendritic cells, activated T- and B-lymphocytes, and lower TNF-α expression in macrophages compared to lupus-prone mice with functional IRAK4. Thus, IRAK4 kinase activity contributes to murine lupus and could represent a new therapeutic target.

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Section: Discussionmentioning

confidence: 89%

“…Since TLR responses are shaped by positive (Pellino‐1) and negative (Pellino‐3, Tollip, IRAK‐M) regulators , we determined the levels of these molecules in macrophages from lupus‐prone and lupus‐resistant mice. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

et al. 2017

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“…In the present study, a bioinformatics analysis was performed to screen the potential targeting genes of miR-21 based on four prediction databases. Among the genes common to all four databases, we selected Peli1, a member of the RING finger E3 ubiquitin ligase family, as a target for further research because of its key role in various immune or inflammatory regulation pathways [28][29][30]. Liu et al [21] and Chang et al [22] reported that Peli1-deficient mice spontaneously developed SLE that was characterized by a severe lupus-like damage and autoantibody production.…”

Section: Discussionmentioning

confidence: 99%

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

Xie

Wang

et al. 2020

Journal of Immunology Research

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Background. Premature ovarian insufficiency (POI) represents the hypergonadotropic hypoestrogenic symptoms that result in the loss of ovarian follicles. 5-30% POI cases are suggested to be involved in autoimmune etiology. MicroRNA-21 (miR-21) plays a vital role in ovarian folliculogenesis via regulating and interacting with multiple target genes. Here, we conduct the target prediction of miR-21, identify the expression and correlation of miR-21 and its putative target Pellino-1 (Peli1), and confirm their relationship with clinical characteristics in autoimmune POI. Methods. Bioinformatic analysis was conducted to screen the miR-21 putative target gene. Autoimmune POI mouse models were established by ZP3 immunization. Serum miR-21, Peli1 mRNA of peripheral blood mononuclear cells (PBMCs) and regulatory T cells (Tregs), general status, spleen Tregs ratio, inflammatory factors, ovarian endocrine function, and ovarian structure were evaluated. For autoimmune POI patients, serum miR-21, PBMCs Peli1 mRNA levels, general data, immune parameters, hormone levels, and ultrasound examinations were obtained. The correlations of miR-21 with Peli1 and clinical characteristics in patients were analyzed. Results. Peli1 was selected based on four microRNA prediction databases and literature retrieval. In mouse models, serum miR-21 level, PBMCs and Tregs Peli1 mRNA, and spleen Tregs ratio were 0.61±0.09, 0.12±0.12, 0.27±0.23 and 4.82±0.58, respectively, lower than those in the control group. In patients, miR-21 level (0.60±0.14) and Peli1 mRNA (0.30±0.14) were lower than those in the control group (1.01±0.07 and 1.63±0.54); miR-21 was positively related with Peli1, AMH, E2, the size of the uterus, and ovarian volume and negatively related with FSH, LH, and the number of positive immune parameters (AOAb, EMAb, ACL, ANA, ds-DNA, ACA, IgG, IgA, IgM, IgE, C3, and C4). Conclusions. Low expressions of miR-21 and Peli1 were detected in autoimmune POI mice and patients. Positive correlation between miR-21 and Peli1 was observed in autoimmune POI patients, suggesting that miR-21 and Peli1 might be associated with the pathogenesis of autoimmune POI.

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“…E3 ubiquitin ligases have been reported to be involved in the regulation of RIG-I signaling (14,15). For example, E3 ubiquitin ligases TRIM25, Riplet, and MEX3C can mediate K63-linked polyubiquitination of human RIG-I (10,(16)(17)(18)(19), thus positively regulating RIG-I-mediated signaling.…”

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confidence: 99%

RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation

Wang

Jiang

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-Iinteracting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48-linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I-triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity.RIG-I | E3 ligase | RNF122 | innate immunity | type I interferon

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E3 ubiquitin ligases Pellinos as regulators of pattern recognition receptor signaling and immune responses

Cited by 52 publications

References 114 publications

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

miR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency

RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation

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