Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Janna Schneppenheim - , Kiel University (Author)
  • Susann Hüttl - , Kiel University (Author)
  • Anne Kruchen - , Research Institute Children's Cancer Center Hamburg (Author)
  • Regina Fluhrer - , Ludwig Maximilian University of Munich, German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Ingo Müller - , University of Hamburg (Author)
  • Paul Saftig - , Kiel University (Author)
  • Reinhard Schneppenheim - , University of Hamburg (Author)
  • Christa L. Martin - , Geisinger Medical Center (Author)
  • Bernd Schröder - , Institute of Physiological Chemistry, Kiel University (Author)

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.

Details

Original languageEnglish
Pages (from-to)48-53
Number of pages6
JournalBiochemical and biophysical research communications
Volume451
Issue number1
Publication statusPublished - 15 Aug 2014
Peer-reviewedYes

External IDs

PubMed 25035924

Keywords

Keywords

  • B cell maturation, CD74, Common variable immune deficiency, Intramembrane proteolysis, Invariant chain, Signal-peptide-peptidase-like protease