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The intramembrane proteases signal Peptide peptidase-like 2a and 2b have distinct functions in vivo
- Source :
- Molecular and cellular biology 34(8), 1398-1411 (2014). doi:10.1128/MCB.00038-14
- Publication Year :
- 2014
- Publisher :
- Soc., 2014.
-
Abstract
- 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.
- Subjects :
- Signal peptide
Proteases
Proteolysis
medicine.medical_treatment
SPPL2a protein, mouse
Biology
invariant chain
03 medical and health sciences
Mice
ddc:570
metabolism [Dendritic Cells]
SPPL2B
medicine
Animals
Aspartic Acid Endopeptidases
ddc:610
SPPL2b protein, mouse
metabolism [B-Lymphocytes]
Molecular Biology
B cell
030304 developmental biology
Mice, Knockout
B-Lymphocytes
0303 health sciences
Protease
medicine.diagnostic_test
030302 biochemistry & molecular biology
Histocompatibility Antigens Class II
Brain
Membrane Proteins
Articles
Dendritic Cells
Cell Biology
metabolism [Aspartic Acid Endopeptidases]
Antigens, Differentiation, B-Lymphocyte
Dendritic cell homeostasis
genetics [Membrane Proteins]
medicine.anatomical_structure
Biochemistry
metabolism [Antigens, Differentiation, B-Lymphocyte]
genetics [Aspartic Acid Endopeptidases]
metabolism [Brain]
signal peptide peptidase
Heterologous expression
metabolism [Histocompatibility Antigens Class II]
metabolism [Membrane Proteins]
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Molecular and cellular biology 34(8), 1398-1411 (2014). doi:10.1128/MCB.00038-14
- Accession number :
- edsair.doi.dedup.....290f81def68c61c187030a7631e89458