Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

J Immunol. 2015 Aug 15;195(4):1548-63. doi: 10.4049/jimmunol.1403171. Epub 2015 Jul 8.

Abstract

The invariant chain (CD74), a chaperone in MHC class II-mediated Ag presentation, is sequentially processed by different endosomal proteases. We reported recently that clearance of the final membrane-bound N-terminal fragment (NTF) of CD74 is mediated by the intramembrane protease signal peptide peptidase-like (SPPL)2a, a process critical for B cell development. In mice, SPPL2a deficiency provokes the accumulation of this NTF in endocytic vesicles, which leads to a B cell maturation arrest at the transitional 1 stage. To define the underlying mechanism, we analyzed the impact of SPPL2a deficiency on signaling pathways involved in B cell homeostasis. We demonstrate that tonic as well as BCR-induced activation of the PI3K/Akt pathway is massively compromised in SPPL2a(-/-) B cells and identify this as major cause of the B cell maturation defect in these mice. Altered BCR trafficking induces a reduction of surface IgM in SPPL2a-deficient B cells, leading to a diminished signal transmission via the BCR and the tyrosine kinase Syk. We provide evidence that in SPPL2a(-/-) mice impaired BCR signaling is to a great extent provoked by the accumulating CD74 NTF, which can interact with the BCR and Syk, and that impaired PI3K/Akt signaling and reduced surface IgM are not directly linked processes. In line with disturbances in PI3K/Akt signaling, SPPL2a(-/-) B cells show a dysregulation of the transcription factor FOXO1, causing elevated transcription of proapoptotic genes. We conclude that SPPL2a-mediated processing of CD74 NTF is indispensable to maintain appropriate levels of tonic BCR signaling to promote B cell maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / chemistry
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Apoptosis / genetics
  • Aspartic Acid Endopeptidases / deficiency
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Membrane / metabolism
  • Endocytosis / genetics
  • Endocytosis / immunology
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / metabolism
  • Histocompatibility Antigens Class II / chemistry
  • Histocompatibility Antigens Class II / metabolism*
  • Immunoglobulin M / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphocyte Activation
  • MAP Kinase Signaling System
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • NF-kappa B p52 Subunit / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Precursor Cells, B-Lymphoid / cytology
  • Precursor Cells, B-Lymphoid / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction*
  • Syk Kinase

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Histocompatibility Antigens Class II
  • Immunoglobulin M
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NF-kappa B
  • NF-kappa B p52 Subunit
  • Receptors, Antigen, B-Cell
  • invariant chain
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • Syk protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Aspartic Acid Endopeptidases
  • SPPL2a protein, mouse