The miR-155-PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation

J Exp Med. 2014 Oct 20;211(11):2183-98. doi: 10.1084/jem.20140338. Epub 2014 Oct 6.

Abstract

A single microRNA (miRNA) can regulate the expression of many genes, though the level of repression imparted on any given target is generally low. How then is the selective pressure for a single miRNA/target interaction maintained across long evolutionary distances? We addressed this problem by disrupting in vivo the interaction between miR-155 and PU.1 in mice. Remarkably, this interaction proved to be key to promoting optimal T cell-dependent B cell responses, a previously unrecognized role for PU.1. Mechanistically, miR-155 inhibits PU.1 expression, leading to Pax5 down-regulation and the initiation of the plasma cell differentiation pathway. Additional PU.1 targets include a network of genes whose products are involved in adhesion, with direct links to B-T cell interactions. We conclude that the evolutionary adaptive selection of the miR-155-PU.1 interaction is exercised through the effectiveness of terminal B cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Antibody Formation / genetics
  • Antibody Formation / immunology
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Base Sequence
  • Binding Sites
  • Cell Adhesion / genetics
  • Cell Communication / genetics
  • Cell Communication / immunology
  • Cell Differentiation / genetics*
  • Gene Expression Regulation
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Lymphopoiesis / genetics
  • Mice
  • Mice, Knockout
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • Myelopoiesis / genetics
  • PAX5 Transcription Factor / chemistry
  • PAX5 Transcription Factor / genetics*
  • Positive Regulatory Domain I-Binding Factor 1
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*
  • Transcription Factors / genetics

Substances

  • 3' Untranslated Regions
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • PAX5 Transcription Factor
  • Pax5 protein, mouse
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1
  • Positive Regulatory Domain I-Binding Factor 1