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The RNA-binding Protein HuR Controls Thymocyte Development, Selection and Migration

ABSTRACT: The progressive development of T-cells in the thymus is a highly regulated process that aims to arm the body with T-cells against pathogens whilst maintaining tolerance to self. Although the role of gene transcription in this process has been extensively studied, little is known about the significance of associated post-transcriptional mechanisms. Post-transcriptional control is imposed by the dynamic interactions of RNA-binding proteins (RBPs) with RNA molecules which destine mRNA molecules towards translation or destruction. In this study we focus on the functions of an RBP called HuR. We made use of novel transgenic systems in which HuR is deleted in thymic T-cells to test whether HuR is involved in their developmental maturation. We show that HuR controls the generation and provision of T-cells competent for the proper recognition of antigens in the body and the elimination of harmfull cells. We further show that HuR controls T-cell development through its involvement in basic cellular processes like cell cycle regulation, cellular activation, death and migration which were associated to HuR’s efficacy in regulating the expression or function of key signaling components. Our studies provide important insight on the post-transcriptional regulation of fundamental cellular processes and identify HuR as an important modulator of adaptive immunity and autoimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE9174 | GEO | 2009/05/20

SECONDARY ACCESSION(S): PRJNA102737

REPOSITORIES: GEO

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Project description:IL-20 cytokines are involved in the establishment of psoriasis, a common chronic skin inflammation epidemiologically associated with metabolic syndrome, but molecular mechanisms underlying their over-expression remain to be elucidated. We find that keratinocytes (KCs) expressed IL-20 and lymphocytes expressed IL-22 cytokines up-regulation occurs at post-transcriptional level with stabilization of their RNA messengers. Looking at psoriatic epidermis, we observe that the p38/MK2 pathway is not activated but that the RNA-binding protein (RBP) HuR re-localizes in keratinocytes cytoplasm, suggesting post-transcriptional regulation of numerous mRNAs. HuR ribonucleoprotein immunoprecipitations analyzed by high-throughput sequencing (RIP-Seq) identify potential pre-mature and mature RNA targets for uninvolved and involved skin and confirms that HuR activity is displaced from the nucleus to the cytoplasm. Numerous psoriasis up-regulated transcripts are HuR targets and HuR knockdown reduces expression of transcripts like beta-defensin-2, CXCL-10 or IL-2, suggesting an implication of HuR in pathophysiological processes such as morphological, immune and metabolic inflammatory responses. Finally, metabolic disorders affecting psoriatic keratinocytes are responsible for HuR cytoplasmic localization since a decreased activity of the cellular metabolic sensor AMPK, that is observed in human psoriatic epidermis, is sufficient to promote HuR cytosolic localization as well as IL-20 over-production both in human keratinocytes and in vivo in mouse epidermis where it then initiates psoriasis-like histological changes. These results may provide insights into molecular links between metabolism and post-transcriptional networks during chronic inflammation, as illustrated in psoriasis by mechanisms connecting AMPK, HuR and IL-20. Analysis of HuR-binding RNA in uninvolved versus involved psoriatic samples by RIP-Seq. Samples from five different patients were used for both uninvolved and involved skin. RIP-Seq was also made using a control IgG.

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The RNA-binding Protein HuR Controls Thymocyte Development, Selection and Migration

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