Interferon-α Induces Up-regulation and Nuclear Translocation of the Ro52 Autoantigen as Detected by a Panel of Novel Ro52-specific Monoclonal Antibodies

Strandberg, Linn; Ambrosi, Aurélie; Espinosa, Alexander; Ottosson, Lars; Eloranta, Maija‐Leena; Zhou, Wei; Elfving, Åse; Greenfield, Edward; Kuchroo, Vijay K.; Wahren‐Herlenius, Marie

doi:10.1007/s10875-007-9157-0

Cited by 106 publications

(120 citation statements)

References 35 publications

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“…It has previously been reported that Trim21 expression is induced by both type I and type II IFNs in a variety of cells (20,21,41,42). We confirmed and extended these data by using a mouse T cell line and observed that Trim21 expression is indeed induced by IFNs in a dose-dependent manner and that type I IFNs (especially IFN-b) are more potent at inducing Trim21 transcription than IFN-g (Fig.…”

Section: Ifn-a and Ifn-b Are Potent Inducers Of Trim21 In A Variety Osupporting

confidence: 86%

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Sjöstrand

Ambrosi

Brauner

et al. 2013

The Journal of Immunology

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Tripartite-motif 21 (TRIM21) is an E3 ubiquitin ligase that regulates innate immune responses by ubiquitinating IFN regulatory factors (IRFs). TRIM21 is mainly found in hematopoietic cells in which its expression is induced by IFNs during viral. infections and in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren’s syndrome. However, the exact molecular mechanism by which the expression of the Trim21 gene is regulated is unknown. In this study, we demonstrate that IFNs induce Trim21 expression in immune cells via IRFs and that IFN-α and IFN-β are the most potent inducers of Trim21. A functional IFN-stimulated response element but no conserved IFN-γ–activated site was detected in the promoter of Trim21. IRF1 and IRF2 strongly induced Trim21 expression in an IFN-stimulated response element–dependent manner, whereas IRF4 and IRF8 strongly repressed the IRF1-mediated induction of Trim21. Consistent with this observation, baseline expression of Trim21 was elevated in Irf4−/− cells. TRIM21, IRF1, and IRF2 expression was increased in PBMCs from patients with Sjögren’s syndrome compared with healthy controls. In contrast, IRF4 and IRF8 expression was not increased in PBMCs from patients. The IFN-γ–mediated induction of Trim21 was completely abolished by inhibiting protein synthesis with cycloheximide, and Trim21 expression could not be induced by IFN-γ in Irf1−/− cells, demonstrating that IFN-γ induces Trim21 indirectly via IRF1 and not directly via STAT1 activation. Our data demonstrate that multiple IRFs tightly regulate expression of Trim21 in immune cells, suggesting that a well-controlled expression of the E3 ligase TRIM21 is important for regulation of immune responses.

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Section: Ifn-a and Ifn-b Are Potent Inducers Of Trim21 In A Variety Osupporting

confidence: 86%

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Sjöstrand

Ambrosi

Brauner

et al. 2013

The Journal of Immunology

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“…The UBED1-4 class I E2s are cytoplasmic, whereas UBE2E1-2 class III E2s are localized to the cell nucleus (32,40). This cellular compartmentalization of E2s may contribute to both temporal and substrate specificity of the ubiquitination process, as Ro52 is predominantly cytoplasmic (1, 7), but translocates into the nucleus upon interferon stimulation (1).…”

Section: Discussionmentioning

confidence: 99%

“…The study was approved by the Regional Human Ethics Committee at the Karolinska University Hospital, and informed consent was obtained from all subjects. Monoclonal antibodies against human Ro52 were generated by standard hybridoma protocols and characterized as described previously (1,22).…”

Section: Methodsmentioning

confidence: 99%

“…All data sets were processed using NMRPipe (25) and analyzed using CARA. Sequential resonance assignments for RING-RBL were obtained from three-dimensional 1 (26) with a water flip-back pulse for water suppression. Attempts at purifying the RING-RBL at pH 6 after Ni-NTA purification as well as screening of a wide range of different buffer systems failed.…”

Section: Methodsmentioning

confidence: 99%

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Anti-Ro52 Autoantibodies from Patients with Sjögren's Syndrome Inhibit the Ro52 E3 Ligase Activity by Blocking the E3/E2 Interface

Espinosa

Hennig

Ambrosi

et al. 2011

Journal of Biological Chemistry

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Ro52 (TRIM21)is an E3 ligase of the tripartite motif family that negatively regulates proinflammatory cytokine production by ubiquitinating transcription factors of the interferon regulatory factor family. Autoantibodies to Ro52 are present in patients with lupus and Sjögren's syndrome, but it is not known if these autoantibodies affect the function of Ro52. To address this question, the requirements for Ro52 E3 ligase activity were first analyzed in detail. Scanning a panel of E2 ubiquitin-conjugating enzymes, we found that UBE2D1-4 and UBE2E1-2 supported the E3 ligase activity of Ro52 and that the E3 ligase activity of Ro52 was dependent on its RING domain. We also found that the N-terminal extensions in the class III E2 enzymes affected their interaction with Ro52. Although the N-terminal extension in UBE2E3 made this E2 enzyme unable to function together with Ro52, the N-terminal extensions in UBE2E1 and UBE2E2 allowed for a functional interaction with Ro52. AntiRo52-positive patient sera and affinity-purified anti-RING domain autoantibodies inhibited the E3 activity of Ro52 in ubiquitination assays. Using NMR, limited proteolysis, ELISA, and Ro52 mutants, we mapped the interactions between Ro52, UBE2E1, and anti-Ro52 autoantibodies. We found that antiRo52 autoantibodies inhibited the E3 ligase activity of Ro52 by sterically blocking the E2/E3 interaction between Ro52 and UBE2E1. Our data suggest that anti-Ro52 autoantibodies binding the RING domain of Ro52 may be actively involved in the pathogenesis of rheumatic autoimmune disease by inhibiting Ro52-mediated ubiquitination.Ro52 (TRIM21) is an interferon-inducible protein frequently targeted by autoantibodies in patients with primary Sjögren's syndrome (SS) 4 and systemic lupus erythematosus (SLE) (1, 2). As a member of the tripartite motif (TRIM) protein family (3), Ro52 is characterized by a RING domain (4), a B-box type 2 motif (5), and a coiled-coil region. A B30.2 domain is located in the C-terminal region (6). Several TRIM family members, including Ro52, have been identified as E3 ubiquitin ligases involved in the ubiquitination process (7-10). Ubiquitination is a covalent post-translational modification of proteins by the 76-amino acid residue polypeptide ubiquitin, leading either to proteolysis in the proteasome, internalization from membranes, or functional alteration (11,12). After activation by a ubiquitin-activating enzyme (E1), ubiquitin is transferred to a ubiquitin-conjugating enzyme (E2) followed by a ubiquitin ligase (E3)-mediated transfer of ubiquitin from the E2 to a target protein (13). Ro52 mediates ubiquitination of several members of the interferon regulatory factor (IRF) transcription factor family, thereby regulating cytokine production (14 -17). Gene disruption of Ro52 leads to increased production of proinflammatory cytokines by embryonic fibroblasts and immune cells after Toll-like receptor activation, suggesting that Ro52 negatively regulates IRF activity (16,17).Autoantibodies to Ro52 can appear years before tissue damage is ...

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“…Although the autoantibodies are found primarily in the sera of patients with Systemic Lupus Erythematosus (SLE) and Sj€ ogren's Syndrome (SS), they are also found in patients with other systemic autoimmune diseases such as rheumatoid arthritis and systemic sclerosis. [64][65][66][67][68] While the role of TRIM21…”

Section: Spry/b302 Domain-containing Proteins Involved In Innate Celmentioning

confidence: 99%

Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity

et al. 2012

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The SPRY domain is a protein interaction module found in 77 murine and 100 human proteins, and is implicated in important biological pathways, including those that regulate innate and adaptive immunity. The current definition of the SPRY domain is based on a sequence repeat discovered in the splA kinase and ryanodine receptors. The greater SPRY family is divided into the B30.2 (which contains a PRY extension at the N-terminus) and ''SPRY-only'' sub-families. In this brief review, we examine the current structural and biochemical literature on SPRY/B30.2 domain involvement in key immune processes and highlight a PRY-like 60 amino acid region in the N-terminus of ''SPRY-only'' proteins. Phylogenetic, structural, and functional analyses suggest that this N-terminal region is related to the PRY region of B30.2 and should be characterized as part of an extended SPRY domain. Greater understanding of the functional importance of the N-terminal region in ''SPRY only'' proteins will enhance our ability to interrogate SPRY interactions with their respective binding partners.Keywords: SPRY domain; PRY; B30.2 domain; TRIM; BTN; SPSB; SOCS box; IgG; innate immunity; structure/function Abbreviations: Ash2L, ash2 (absent, small, or homeotic)-like; BTN, butyrophilin; DDX1, DEAD (Asp-Glu-Ala-Asp) box helicase 1; hnRNP, heterogeneous nuclear ribonucleoprotein; iNOS, inducible nitric oxide synthase; MID1, midline 1; RIG-I, retinoic acid-inducible gene I; HIV, human immunodeficiency virus; MEFV, Mediterranean fever; MLV, murine leukemia virus; NMR, nuclear magnetic resonance; IRF, interferon regulatory factor; NFjB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; NO, nitric oxide; FMF, familial Mediterranean fever; Fbxo45, F-box protein 45; IgG, immunoglobulin G; PYD, pyrin domain; RNF135, ring finger protein 135; Rbx2, RING box protein 2; RyR, ryanodine receptor; RING, really interesting new gene; RBCC, RING/B-box/coiled coil; SPRY, in splA kinase and ryanodine receptor; SOCS, suppressor of cytokine signaling; SPSB, SPRY domain-containing SOCS box; TRIM, tripartite motif; TLRs, toll-like receptors.

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Interferon-α Induces Up-regulation and Nuclear Translocation of the Ro52 Autoantigen as Detected by a Panel of Novel Ro52-specific Monoclonal Antibodies

Cited by 106 publications

References 35 publications

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Anti-Ro52 Autoantibodies from Patients with Sjögren's Syndrome Inhibit the Ro52 E3 Ligase Activity by Blocking the E3/E2 Interface

Structure and function of the SPRY/B30.2 domain proteins involved in innate immunity

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