title: The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain.
abstract: Regulated intramembrane proteolysis is a central cellular process involved in signal transduction and membrane protein turnover. The presenilin homologue signal-peptide-peptidase-like 2a (SPPL2a) has been implicated in the cleavage of type 2 transmembrane proteins. We show that the invariant chain (li, CD74) of the major histocompatability class II complex (MHCII) undergoes intramembrane proteolysis mediated by SPPL2a. B lymphocytes of SPPL2a(-/-) mice accumulate an N-terminal fragment (NTF) of CD74, which severely impairs membrane traffic within the endocytic system and leads to an altered response to B cell receptor stimulation, reduced BAFF-R surface expression, and accumulation of MHCII in transitional developmental stage T1 B cells. This results in significant loss of B cell subsets beyond the T1 stage and disrupted humoral immune responses, which can be recovered by additional ablation of CD74. Hence, we provide evidence that regulation of CD74-NTF levels by SPPL2a is indispensable for B cell development and function by maintaining trafficking and integrity of MHCII-containing endosomes, highlighting SPPL2a as a promising pharmacological target for depleting and/or modulating B cells.
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, D-24118 Kiel, Germany.
authors.forename: Janna
authors.initials: J
authors.lastname: Schneppenheim
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.forename: Susann
authors.initials: S
authors.lastname: Hüttl
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.forename: Kai
authors.initials: K
authors.lastname: Dittmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.forename: Eeva-Liisa
authors.initials: EL
authors.lastname: Eskelinen
authors.forename: Irm
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.forename: Regina
authors.initials: R
authors.lastname: Fluhrer
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D001483:Base Sequence; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D021381:Protein Transport; D014617:Vacuoles / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D053265:B-Cell Activation Factor Receptor; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; D010446:Peptide Fragments; C486662:Tnfrsf13c protein, mouse; C045084:invariant chain; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse