Roquin-2 Shares Functions with Its Paralog Roquin-1 in the Repression of mRNAs Controlling T Follicular Helper Cells and Systemic Inflammation

Accumulation of T follicular helper (Tfh) cells and proinflammatory cytokines drive autoantibody-mediated diseases. The RNA-binding protein Roquin-1 (Rc3h1) represses the inducible costimulator ICOS and interferon-γ (IFN-γ) in T cells to prevent Tfh cell accumulation. Unlike Rc3h1san mice with a mut...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2013-04, Vol.38 (4), p.669-680
Main Authors: Pratama, Alvin, Ramiscal, Roybel R., Silva, Diego G., Das, Souvik K., Athanasopoulos, Vicki, Fitch, Jessica, Botelho, Natalia K., Chang, Pheh-Ping, Hu, Xin, Hogan, Jennifer J., Maña, Paula, Bernal, David, Korner, Heinrich, Yu, Di, Goodnow, Christopher C., Cook, Matthew C., Vinuesa, Carola G.
Format: Article
Language:English
Subjects:
Adaptive Immunity - genetics
Animals
Antibody Formation - genetics
Cell Line
Experiments
Genes
Histology
Immunity, Innate - genetics
Inducible T-Cell Co-Stimulator Protein - metabolism
Mice
Mice, Mutant Strains
Mutation - genetics
Proteins
Repressor Proteins - genetics
Repressor Proteins - metabolism
RING Finger Domains - genetics
RNA, Messenger - metabolism
Rodents
Scholarships & fellowships
Statistical analysis
T-Lymphocytes, Helper-Inducer - immunology
Tumor Necrosis Factor-alpha - immunology
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:Accumulation of T follicular helper (Tfh) cells and proinflammatory cytokines drive autoantibody-mediated diseases. The RNA-binding protein Roquin-1 (Rc3h1) represses the inducible costimulator ICOS and interferon-γ (IFN-γ) in T cells to prevent Tfh cell accumulation. Unlike Rc3h1san mice with a mutation in the ROQ domain of Roquin-1, mice lacking the protein, paradoxically do not display increased Tfh cells. Here we have analyzed mice with mutations that eliminate the RING domain from Roquin-1 or its paralog, Roquin-2 (Rc3h2). RING or ROQ mutations both disrupted Icos mRNA regulation by Roquin-1, but, unlike the ROQ mutant that still occupied mRNA-regulating stress granules, RING-deficient Roquin-1 failed to localize to stress granules and allowed Roquin-2 to compensate in the repression of ICOS and Tfh cells. These paralogs also targeted tumor necrosis factor (TNF) in nonlymphoid cells, ameliorating autoantibody-induced arthritis. The Roquin family emerges as a posttranscriptional brake in the adaptive and innate phases of antibody responses. ► Roquin-1 and Roquin-2 repress Icos mRNA and Tfh cells ► Roquin-2 compensates for Roquin-1 defect when Roquin-1 is absent from SGs ► Roquin-1 and Roquin-2 act in macrophages to repress TNF ► The Roquin paralogs curtail septic shock and autoantibody-dependent arthritis
ISSN:1074-7613
1097-4180
DOI:10.1016/j.immuni.2013.01.011