Igβ ubiquitination activates PI3K signals required for endosomal sorting

J Exp Med. 2017 Dec 4;214(12):3775-3790. doi: 10.1084/jem.20161868. Epub 2017 Nov 15.

Abstract

A wealth of in vitro data has demonstrated a central role for receptor ubiquitination in endocytic sorting. However, how receptor ubiquitination functions in vivo is poorly understood. Herein, we report that ablation of B cell antigen receptor ubiquitination in vivo uncouples the receptor from CD19 phosphorylation and phosphatidylinositol 3-kinase (PI3K) signals. These signals are necessary and sufficient for accumulating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) on B cell receptor-containing early endosomes and proper sorting into the MHC class II antigen-presenting compartment (MIIC). Surprisingly, MIIC targeting is dispensable for T cell-dependent immunity. Rather, it is critical for activating endosomal toll-like receptors and antiviral humoral immunity. These findings demonstrate a novel mechanism of receptor endosomal signaling required for specific peripheral immune responses.

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • CD79 Antigens / metabolism*
  • Endocytosis
  • Endosomes / metabolism*
  • Histocompatibility Antigens Class II / metabolism
  • Immunity, Humoral
  • Male
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphatidylinositol Phosphates / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction*
  • Toll-Like Receptors / metabolism
  • Ubiquitin / metabolism
  • Ubiquitination*

Substances

  • CD79 Antigens
  • Histocompatibility Antigens Class II
  • Phosphatidylinositol Phosphates
  • Receptors, Antigen, B-Cell
  • Toll-Like Receptors
  • Ubiquitin
  • phosphatidylinositol 3-phosphate
  • Phosphatidylinositol 3-Kinase