The intramembrane proteases signal Peptide peptidase-like 2a and 2b have distinct functions in vivo.
We reported recently that the presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is essential for B cell development by cleaving the N-terminal fragment (NTF) of the invariant chain (li, CD74). Based on this, we suggested that pharmacological modulation of SPPL2a may represent a novel approach to deplete B cells in autoimmune disorders. With regard to reported overlapping substrate spectra of SPPL2a and its close homologue, SPPL2b, we investigated the role of SPPL2b in CD74 NTF proteolysis and its impact on B and dendritic cell homeostasis. In heterologous expression experiments, SPPL2b was found to cleave CD74 NTF with an efficiency similar to that of SPPL2a. For in vivo analysis, SPPL2b single-deficient and SPPL2a/SPPL2b double-deficient mice were generated and examined for CD74 NTF turnover/accumulation, B cell maturation and functionality, and dendritic cell homeostasis. We demonstrate that in vivo SPPL2b does not exhibit a physiologically relevant contribution to CD74 proteolysis in B and dendritic cells. Furthermore, we reveal that both proteases exhibit divergent subcellular localizations in B cells and different expression profiles in murine tissues. These findings suggest distinct functions of SPPL2a and SPPL2b and, based on a high abundance of SPPL2b in brain, a physiological role of this protease in the central nervous system.
Biochemical Institute, Christian Albrechts University of Kiel, Kiel, Germany.
Janna
J
Schneppenheim
Susann
S
Hüttl
Torben
T
Mentrup
Renate
R
Lüllmann-Rauch
Michelle
M
Rothaug
Michael
M
Engelke
Kai
K
Dittmann
Ralf
R
Dressel
Masatake
M
Araki
Kimi
K
Araki
Jürgen
J
Wienands
Regina
R
Fluhrer
Paul
P
Saftig
Bernd
B
Schröder
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; C045084:invariant chain; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse; C568856:SPPL2b protein, mouse; C460085:signal peptide peptidase