Abstract
miR-185 is a microRNA (miR) that targets Bruton's tyrosine kinase in B cells, with reductions in miR-185 linked to B cell autoantibody production. In hippocampal neurons, miR-185 targets both sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and a novel Golgi inhibitor. This miR is haploinsufficient in 90-95% of individuals with chromosome 22q11.2 deletion syndrome, patients who can present with immune, cardiac, and parathyroid problems, learning disorders, and a high incidence of schizophrenia in adults. The reduced levels of miR-185 in neurons cause presynaptic neurotransmitter release. Many of the 22q11.2 deletion syndrome patients have a thymic hypoplasia, which results in a peripheral T cell lymphopenia and unusual T helper cell skewing. The molecular targets of miR-185 in thymocytes are unknown. Using an miR-185 T cell transgenic approach, increasing levels of miR-185 attenuated T cell development at the T cell receptor β (TCRβ) selection checkpoint and during positive selection. This caused a peripheral T cell lymphopenia. Mzb1, Nfatc3, and Camk4 were identified as novel miR-185 targets. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, whereas a knockdown of miR-185 diminished these calcium responses. These effects concur with reductions in Mzb1, an endoplasmic reticulum calcium regulator. Consistent with their haploinsufficiency of miR-185, Mzb1 levels were elevated in thymocyte extracts from several 22q11.2 deletion syndrome patients. Our findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1.
Highlights
MicroRNAs have critical roles in T cell development under normal and stress conditions
Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, whereas a knockdown of miR185 diminished these calcium responses. These effects concur with reductions in marginal zone B and B1 cell-specific protein (Mzb1), an endoplasmic reticulum calcium regulator
Our findings indicate that miR-185 regulates T cell development through its targeting of several mRNAs including Mzb1
Summary
MicroRNAs have critical roles in T cell development under normal and stress conditions. MiR-185 targets both sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and a novel Golgi inhibitor This miR is haploinsufficient in 90 –95% of individuals with chromosome 22q11.2 deletion syndrome, patients who can present with immune, cardiac, and parathyroid problems, learning disorders, and a high incidence of schizophrenia in adults. Elevations in miR-185 enhanced TCR-dependent intracellular calcium levels, whereas a knockdown of miR185 diminished these calcium responses These effects concur with reductions in Mzb, an endoplasmic reticulum calcium regulator. Elevated miR-185 Impairs T Cell Development ically relevant [15, 16] Mouse models of this syndrome have shown that the haploinsufficiency of miR-185 elevates the expression of one of its neuronal targets, SERCA2 (Sarcoplasmic/ endoplasmic reticulum calcium ATPase 2) [17]. Our findings indicate that alterations in the expression of miR-185 can affect T cell development and activation by controlling the expression of several novel mRNA targets including Mzb
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