Transgenic expression of microRNA-185 causes a developmental arrest of T cells by targeting multiple genes including Mzb1

J Biol Chem. 2013 Oct 18;288(42):30752-30762. doi: 10.1074/jbc.M113.503532. Epub 2013 Sep 6.

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.

Keywords: 22q11.2 Deletion Syndrome; Calcium Intracellular Release; Genetic Diseases; Immunodeficiency; MicroRNA; T Cell Biology; Transcription Target Genes; Transgenic Mice.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Calcium / immunology
  • Calcium / metabolism
  • Calcium Signaling*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / immunology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Cytokines / immunology
  • Humans
  • Mice
  • Mice, Transgenic
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / immunology
  • NFATC Transcription Factors / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Thymocytes / cytology
  • Thymocytes / immunology
  • Thymocytes / metabolism*
  • Transgenes / genetics
  • Transgenes / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • MEDA-7 protein, mouse
  • MIRN185 microRNA, human
  • MZB1 protein, human
  • MicroRNAs
  • Mirn185 microRNA, mouse
  • NFATC Transcription Factors
  • NFATC3 protein, human
  • Nfatc3 protein, mouse
  • RNA, Messenger
  • Receptors, Antigen, T-Cell, alpha-beta
  • CAMK4 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Camk4 protein, mouse
  • Calcium

Associated data

  • GEO/GSE49057