title: Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells.
abstract: The invariant chain (CD74) mediates targeting of the MHCII complex to endosomal compartments, where CD74 undergoes degradation allowing MHCII to acquire peptides. We demonstrated recently that intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalyzed by Signal-peptide-peptidase-like 2a (SPPL2a) and that this process is indispensable for development and function of B lymphocytes in mice. In SPPL2a(-/-) mice, homeostasis of these cells is disturbed by the accumulation of the unprocessed CD74 NTF. So far, evidence for this essential role of SPPL2a is restricted to mice. Nevertheless, inhibition of SPPL2a has been suggested as novel approach to target B cells for treating autoimmunity. Here, we characterize human B cell lines with a homozygous microdeletion on chromosome 15. We demonstrate that this deletion disrupts the SPPL2a genomic locus and leads to loss of SPPL2a transcript. Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a(-/-) mice. By this means, we present evidence that the role of SPPL2a in CD74 proteolysis is conserved in human B cells and provide support for modulation of SPPL2a activity as a therapeutic concept.
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Janna
authors.initials: J
authors.lastname: Schneppenheim
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Hüttl
authors.affiliation: Research Institute Children's Cancer Center, Hamburg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Kruchen
authors.affiliation: Adolf-Butenandt-Institute for Biochemistry, Ludwig Maximilians University of Munich, Munich, Germany; DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Fluhrer
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.affiliation: Autism and Developmental Medicine Institute, Geisinger Health System, Danville, PA, USA.
authors.forename: Christa L
authors.initials: CL
authors.lastname: Martin
authors.affiliation: Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany. Electronic address: baschroeder@biochem.uni-kiel.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002872:Chromosome Deletion; D002884:Chromosomes, Human, Pair 15; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007425:Intracellular Membranes / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; C045084:invariant chain; D016282:Aspartic Acid Endopeptidases; C524670:SPPL2a protein, human
keywords: B cell maturation; CD74; Common variable immune deficiency; Intramembrane proteolysis; Invariant chain; Signal-peptide-peptidase-like protease