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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Janna Schneppenheim - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Susann Hüttl - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Anne Kruchen - , Forschungsinstitut Kinderkrebs-Zentrum Hamburg gGMBH (Autor:in)
  • Regina Fluhrer - , Ludwig-Maximilians-Universität München (LMU), Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Ingo Müller - , Universität Hamburg (Autor:in)
  • Paul Saftig - , Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)
  • Reinhard Schneppenheim - , Universität Hamburg (Autor:in)
  • Christa L. Martin - , Geisinger Medical Center (Autor:in)
  • Bernd Schröder - , Institut für Physiologische Chemie, Christian-Albrechts-Universität zu Kiel (CAU) (Autor:in)

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

OriginalspracheEnglisch
Seiten (von - bis)48-53
Seitenumfang6
FachzeitschriftBiochemical and biophysical research communications
Jahrgang451
Ausgabenummer1
PublikationsstatusVeröffentlicht - 15 Aug. 2014
Peer-Review-StatusJa

Externe IDs

PubMed 25035924

Schlagworte

Schlagwörter

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