title: Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation.
abstract: 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 Rc3h1(san) 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.
authors.affiliation: Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Alvin
authors.initials: A
authors.lastname: Pratama
authors.forename: Roybel R
authors.initials: RR
authors.lastname: Ramiscal
authors.forename: Diego G
authors.initials: DG
authors.lastname: Silva
authors.forename: Souvik K
authors.initials: SK
authors.lastname: Das
authors.forename: Vicki
authors.initials: V
authors.lastname: Athanasopoulos
authors.forename: Jessica
authors.initials: J
authors.lastname: Fitch
authors.forename: Natalia K
authors.initials: NK
authors.lastname: Botelho
authors.forename: Pheh-Ping
authors.initials: PP
authors.lastname: Chang
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hogan
authors.forename: Paula
authors.initials: P
authors.lastname: Maña
authors.forename: David
authors.initials: D
authors.lastname: Bernal
authors.forename: Heinrich
authors.initials: H
authors.lastname: Korner
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D002460:Cell Line; D007113:Immunity, Innate / Q000235:genetics; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D054829:RING Finger Domains / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D012333:RNA, Messenger; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; C582114:roquin-2 protein, mouse; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases