SS-A/Ro52, an Autoantigen Involved in CD28-Mediated IL-2 Production

Ishii, Tomonori; Ohnuma, Kei; Murakami, Akikazu; Takasawa, Naruhiko; Yamochi, Tadanori; Iwata, Satoshi; Uchiyama, M.; Dang, Nam H.; Tanaka, Hirotoshi; Morimoto, Chikao

doi:10.4049/jimmunol.170.7.3653

Cited by 46 publications

(37 citation statements)

References 37 publications

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“…IRF4 is induced by T cell activation via TCR signaling, and the dramatic effects of IRF4 on Trim21 expression suggests that TRIM21 plays a role in T cell biology as previously suggested by Ishii et al (60). The higher expression level of IRF4 in B cells compared with T cells (http://www.immgen.org/databrowser/index.html) could explain the lower basal expression and weaker induction of Trim21 in B cells following IFN stimulation, because IRF4 can repress both the basal and IRF1-induced expression of Trim21.…”

Section: Discussionsupporting

confidence: 52%

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: Discussionsupporting

confidence: 52%

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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“…We showed that SSA directly binds and recruits ER to the promoter of target genes. Our findings of previously unidentified direct involvement of SSA in nuclear receptor-mediated transcription further emphasize its important regulatory roles in cellular physiology, in addition to its previously known ubiquitin-mediated proteasomal regulation of substrate proteins to activate signaling cascades such as NF-B, AP-1, and IRF3 (8,9).…”

Section: Discussionmentioning

confidence: 91%

“…Relevant to its clinical association with autoimmune diseases, SSA has been reported to play dual roles to regulate immune function. SSA enhances antibody-mediated immune responses to pathogens by increasing proinflammatory signaling pathways (8,9). SSA is also required to suppress cytokine production (10,11) as well as innate immune responses to intracellular double-stranded DNA (12).…”

mentioning

confidence: 99%

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

Kang

Jung

Qin

et al. 2014

Molecular and Cellular Biology

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Coactivator activator (CoAA) is a dual-functional coregulator that regulates steroid receptor-mediated transcription and alternative splicing. Previously, we have shown that CoAA has tumor-suppressive potential in tumorigenic human kidney cells. Here, we uncover a molecular mechanism by which Sjogren syndrome-associated autoantigen (SSA), an estrogen receptor (ER) coactivator, induces MYC oncogene by removing repressive CoAA through E2-dependent degradation of CoAA and promotes G 1 /S transition of the cell cycle as well as anchorage-independent growth capability of breast cancer cells. We also show that E2 and ER enhance the E3 ligase activity of SSA to modulate CoAA through splicing isoform-selective ubiquitylation. We propose this as one potential molecular basis for the reduced tumor incidence in autoimmune disease patients and suggest SSA as a potential therapeutic target to treat breast cancer.

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“…HEK293 cells were used to assay for human CD86 promoter activity following CD26-caveolin-1 interaction with Tollip and IRAK-1. Luciferase enzyme activity was determined using a luminometer (Promega), and relative light units were normalized to the protein amount determined with protein assay reagent according to the manufacturer's instructions (Pierce Biotechnology) (22,32,43).…”

mentioning

confidence: 99%

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

Ohnuma

Yamochi

Uchiyama

et al. 2005

Molecular and Cellular Biology

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CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptorassociated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-B. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigenspecific T-cell proliferation.CD26 is a widely distributed 110-kDa cell surface glycoprotein with known dipeptidyl peptidase IV (DPPIV) (EC 3.4.14.5) activity in its extracellular domain (16,38). This enzyme is capable of cleaving amino-terminal dipeptides with either L-proline or L-alanine at the penultimate position. While CD26 expression is enhanced following activation of resting T cells, CD4 ϩ CD26 high T cells respond maximally to recall antigens such as tetanus toxoid (TT) (39). Cross-linking of CD26 and CD3 with solid-phase immobilized monoclonal antibodies (MAbs) can induce T-cell costimulation and interleukin-2 (IL-2) production by either human CD4 ϩ T cells or Jurkat T-cell lines transfected with CD26 cDNA (16,56). In addition, anti-CD26 antibody treatment of T cells leads to a decrease in the surface expression of CD26 via its internalization, and such modulation results in an enhanced proliferative response to anti-CD3 or anti-CD2 stimulation as well as enhanced tyrosine phosphorylation of signaling molecules such as CD3 and p56-Lck (19). Moreover, we showed that DPPIV enzyme activity is required for CD26-mediated T-cell costimulation and various immune responses (23,45,58). We have recently shown that internalization of CD26 after cross-linking is mediated in part by the mannose-6-phosphate/insulin-like growth factor II receptor and that the interaction of CD26 and the mannose-6-phosphate/insulin-like growth factor II receptor plays a role in CD26-induced T-cell costimulation (20).In a recent study, we demonstrated that caveolin-1 is a binding protein of CD26 and that CD26 on activated memory T cells interacts with caveolin-1 on TT-loaded monocytes (43). In this interaction, the scaffolding domain (SCD) of caveolin-1, comprising residues 82 to 101...

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SS-A/Ro52, an Autoantigen Involved in CD28-Mediated IL-2 Production

Cited by 46 publications

References 37 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

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

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SS-A/Ro52, an Autoantigen Involved in CD28-Mediated IL-2 Production

Cited by 46 publications

References 37 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

E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G1/S Arrest To Promote Breast Tumorigenicity

CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

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E2/Estrogen Receptor/Sjogren Syndrome-Associated Autoantigen Relieves Coactivator Activator-Induced G₁/S Arrest To Promote Breast Tumorigenicity