1. Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells
- Author
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Ingo Müller, Bernd Schröder, Regina Fluhrer, Paul Saftig, Anne Kruchen, Reinhard Schneppenheim, Susann Hüttl, Christa Lese Martin, and Janna Schneppenheim
- Subjects
genetics [Antigens, Differentiation, B-Lymphocyte] ,CD74 ,Endosome ,Proteolysis ,Biophysics ,Biology ,medicine.disease_cause ,Biochemistry ,metabolism [Intracellular Membranes] ,Article ,Autoimmunity ,Cell Line ,invariant chain ,Chromosome 15 ,ddc:570 ,medicine ,metabolism [Peptide Fragments] ,Aspartic Acid Endopeptidases ,Humans ,ddc:610 ,metabolism [B-Lymphocytes] ,Molecular Biology ,B-Lymphocytes ,Chromosomes, Human, Pair 15 ,medicine.diagnostic_test ,Common variable immunodeficiency ,genetics [Immunologic Deficiency Syndromes] ,Homozygote ,Histocompatibility Antigens Class II ,Immunologic Deficiency Syndromes ,Cell Biology ,Intracellular Membranes ,metabolism [Aspartic Acid Endopeptidases] ,medicine.disease ,Molecular biology ,genetics [Peptide Fragments] ,Peptide Fragments ,Antigens, Differentiation, B-Lymphocyte ,pathology [B-Lymphocytes] ,Cell culture ,metabolism [Antigens, Differentiation, B-Lymphocyte] ,genetics [Aspartic Acid Endopeptidases] ,SPPL2a protein, human ,metabolism [Histocompatibility Antigens Class II] ,Chromosome Deletion ,Homeostasis ,genetics [Histocompatibility Antigens Class II] - 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.
- Published
- 2014