Abstract
Activation of the β2 integrin lymphocyte function-associated antigen-1 (LFA-1) in T cells induces stabilization of proinflammatory AU-rich element (ARE)-bearing mRNAs, by triggering the nuclear-to-cytoplasmic translocation of the mRNA-binding and -stabilizing protein HuR. However, the mechanism by which LFA-1 engagement controls HuR localization is not known. Here, we identify and characterize four key regulators of LFA-1-induced changes in HuR activity: the p38 pathway kinase MK2 and the constitutive nuclear proteins hnRNPs C, H1 and K. LFA-1 engagement results in rapid, sequential activation of p38 and MK2. Post-LFA-1 activation, MK2 inducibly associates with both hnRNPC and HuR, resulting in the dissociation of HuR from hnRNPs C, H1 and K. Freed from the three hnRNPs, HuR translocates from the nucleus to the cytoplasm, and mediates the stabilization of labile cytokine transcripts. Our results suggest that the modulation of T cell cytokine mRNA half-life is an intricate process that is negatively regulated by hnRNPs C, H1 and K and requires MK2 as a critical activator.
Highlights
Integrin receptor engagement is essential for leukocyte extravasation at sites of infection and inflammation
We have previously shown that T cell lymphocyte function-associated antigen-1 (LFA-1) engagement triggers signaling events that lead to significant stabilization of constitutively labile mRNA transcripts, including TNF-α, IFN-γ, GM-CSF and IL-3, that bear adenylate-uridylate (AU)-rich elements (AREs) in their 3’ untranslated regions (UTRs) [5,6]
If MAP kinase-activated protein kinase 2 (MK2) is a critical effector of LFA-1-induced cytokine transcript stabilization, this should be reflected in its requirement in integrin-triggered Hu protein R (HuR) translocation
Summary
Integrin receptor engagement is essential for leukocyte extravasation at sites of infection and inflammation. Β2 integrins play key roles in forming immunological synapses and macromolecular complexes consisting of both structural and signaling proteins. Kinase signaling and nuclear complex requirements of T cell integrin-induced cytokine mRNA stabilization. National Institutes of Health T32 GM007223 (AW), https://researchtraining.nih.gov/ programs/training-grants/t32; 5. State of Connecticut Department of Public Health AWDS01772 (JB)
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