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

Pratama, Alvin; Ramiscal, Roybel R.; Silva, Diego G.; Das, Sujan Kumar; Athanasopoulos, Vicki; Fitch, Jessica; Botelho, Natalia K.; Chang, Pheh-Ping; Hu, Xin; Hogan, Jennifer J.; Mañá, Paula; Bernal, David García; Korner, Heinrich; Yu, Di; Goodnow, Christopher C.; Cook, Matthew C.; Vinuesa, Carola G.

doi:10.1016/j.immuni.2013.01.011

Cited by 121 publications

(146 citation statements)

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“…The alternative splicing of CD45RA to CD45RO is one of the hallmarks of memory T-cell differentiation (28). The stability of ICOS mRNA, which is governed by the RBPs Roquin-1 and -2, restrains the differentiation of follicular helper T cells (29)(30)(31)(32)(33). The RBPs Zfp36l1 and Zfp36l2 suppress Notch1 mRNA stability, regulating normal thymocyte differentiation and preventing malignant transformation (34).…”

Section: Discussionmentioning

confidence: 99%

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

Chang

Rao

2015

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

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Posttranscriptional regulation is a major mechanism to rewire transcriptomes during differentiation. Heterogeneous nuclear RNA-binding protein LL (hnRNPLL) is specifically induced in terminally differentiated lymphocytes, including effector T cells and plasma cells. To study the molecular functions of hnRNPLL at a genomewide level, we identified hnRNPLL RNA targets and binding sites in plasma cells through integrated Photoactivatable-RibonucleosideEnhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and RNA sequencing. hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3′ untranslated regions (UTRs), promotes exon inclusion or exclusion in a context-dependent manner, and stabilizes mRNA when associated with 3′ UTRs. During differentiation of primary B cells to plasma cells, hnRNPLL mediates a genome-wide switch of RNA processing, resulting in loss of B-cell lymphoma 6 (Bcl6) expression and increased Ig productionboth hallmarks of plasma-cell maturation. Our data identify previously unknown functions of hnRNPLL in B-cell to plasma-cell differentiation and demonstrate that the RNA-binding protein hnRNPLL has a critical role in tuning transcriptomes of terminally differentiating B lymphocytes.

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Section: Discussionmentioning

confidence: 99%

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

Chang

Rao

2015

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

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“…Key components of the early TCR signaling machinery continue to be discovered by genetic and biochemical investigations (113)(114)(115). Rather than the tens of components previously thought to compose the early TCR signal transduction network, affinity purification coupled with mass spectrometry analysis of ZAP-70-, LAT-, and SLP-76-containing protein complexes isolated from primary CD4 + T cells resulted in the identification of a signaling network consisting of 90 signaling proteins, 75% of which had been missed in prior analyses (116).…”

Section: Signaling Nanoclustersmentioning

confidence: 99%

Early T Cell Activation: Integrating Biochemical, Structural, and Biophysical Cues

Malissen

Bongrand

2015

Annu. Rev. Immunol.

120

114

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T cells carry out the formidable task of identifying small numbers of foreign antigenic peptides rapidly and specifically against a very noisy environmental background of endogenous self-peptides. Early steps in T cell activation have thus fascinated biologists and are among the best-studied models of cell stimulation. This remarkable process, critical in adaptive immune responses, approaches and even seems to exceed the limitations set by the physical laws ruling molecular behavior. Despite the enormous amount of information concerning the nature of molecules involved in the T cell antigen receptor (TCR) signal transduction network, and the description of the nanoscale organization and real-time analysis of T cell responses, the general principles of information gathering and processing remain incompletely understood. Here we review currently accepted key data on TCR function, discuss the limitations of current research strategies, and suggest a novel model of TCR triggering and a few promising ways of going further into the integration of available data.

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“…Mammalian genomes encode two roquin paralogs with seemingly redundant functions 4,5 . Human ROQUIN1, also known as RC3H1 (ring finger and CCCH-type zinc finger domains 1), is a 1,133 amino-acid protein, containing a RING (really interesting new gene)-type zinc finger, a roquin domain (ROQ), a CCCH-type zinc finger (zf), and a poorly defined carboxy (C)-terminal, proline-rich domain.…”

mentioning

confidence: 99%

Roquin binding to target mRNAs involves a winged helix-turn-helix motif

et al. 2014

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Roquin proteins mediate mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs via their Roquin domain. Here we present the crystal structure of a Roquin domain, revealing a mostly helical protein fold bearing a winged helix-turn-helix motif. By combining structural, biochemical and mutation analyses, we gain insight into the mode of RNA binding. We show that the winged helix-turn-helix motif is involved in the binding of constitutive decay elements-containing stem-loop mRNAs. Moreover, we provide biochemical evidence that Roquin proteins are additionally able to bind to duplex RNA and have the potential to be functional in different oligomeric states.

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

Cited by 121 publications

References 23 publications

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation

Early T Cell Activation: Integrating Biochemical, Structural, and Biophysical Cues

Roquin binding to target mRNAs involves a winged helix-turn-helix motif

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