title: Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells.
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.
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, D-24118 Kiel, Germany;
authors.forename: Susann
authors.initials: S
authors.lastname: Hüttl
authors.affiliation: BIOSS Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany; Institute for Biology III, Faculty of Biology, University of Freiburg, D-79104 Freiburg, Germany; Max Planck Institute for Immunobiology and Epigenetics, D-79108 Freiburg, Germany;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kläsener
authors.affiliation: Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany;
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Institute of Anatomy, Christian Albrechts University of Kiel, D-24118 Kiel, Germany; and.
authors.forename: Janna
authors.initials: J
authors.lastname: Schneppenheim
authors.affiliation: Institute of Immunology, Christian Albrechts University of Kiel, D-24105 Kiel, Germany.
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.affiliation: Institute of Immunology, Christian Albrechts University of Kiel, D-24105 Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.affiliation: BIOSS Centre for Biological Signalling Studies, University of Freiburg, D-79104 Freiburg, Germany; Institute for Biology III, Faculty of Biology, University of Freiburg, D-79104 Freiburg, Germany; Max Planck Institute for Immunobiology and Epigenetics, D-79108 Freiburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, D-24118 Kiel, Germany;
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, D-24118 Kiel, Germany; baschroeder@biochem.uni-kiel.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D007075:Immunoglobulin M / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000949:Histocompatibility Antigens Class II; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D011947:Receptors, Antigen, B-Cell; C045084:invariant chain; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse