Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells
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Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells. / Schneppenheim, Janna; Hüttl, Susann; Kruchen, Anne; Fluhrer, Regina; Müller, Ingo; Saftig, Paul; Schneppenheim, Reinhard; Martin, Christa L; Schröder, Bernd.
in: BIOCHEM BIOPH RES CO, Jahrgang 451, Nr. 1, 15.08.2014, S. 48-53.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells
AU - Schneppenheim, Janna
AU - Hüttl, Susann
AU - Kruchen, Anne
AU - Fluhrer, Regina
AU - Müller, Ingo
AU - Saftig, Paul
AU - Schneppenheim, Reinhard
AU - Martin, Christa L
AU - Schröder, Bernd
N1 - Copyright © 2014 Elsevier Inc. All rights reserved.
PY - 2014/8/15
Y1 - 2014/8/15
N2 - 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.
AB - 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.
KW - Antigens, Differentiation, B-Lymphocyte
KW - Aspartic Acid Endopeptidases
KW - B-Lymphocytes
KW - Cell Line
KW - Chromosome Deletion
KW - Chromosomes, Human, Pair 15
KW - Histocompatibility Antigens Class II
KW - Homozygote
KW - Humans
KW - Immunologic Deficiency Syndromes
KW - Intracellular Membranes
KW - Peptide Fragments
U2 - 10.1016/j.bbrc.2014.07.051
DO - 10.1016/j.bbrc.2014.07.051
M3 - SCORING: Journal article
C2 - 25035924
VL - 451
SP - 48
EP - 53
JO - BIOCHEM BIOPH RES CO
JF - BIOCHEM BIOPH RES CO
SN - 0006-291X
IS - 1
ER -