Journal Article

DZNE-2020-03266

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The intramembrane protease SPPL2A is critical for tooth enamel formation.

Bronckers, A. L. J. J. (Corresponding author) ; Gueneli, N. ; Lüllmann-Rauch, R. ; Schneppenheim, J. ; Moraru, A. P. ; Himmerkus, N. ; Bervoets, T. J. ; Fluhrer, R.DZNE* ; Everts, V. ; Saftig, P. ; Schröder, B.

2013
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.1002/jbmr.1895

Abstract: Intramembrane proteases are critically involved in signal transduction and membrane protein turnover. Signal-peptide-peptidase-like 2a (SPPL2A), a presenilin-homologue residing in lysosomes/late endosomes, cleaves type II-oriented transmembrane proteins. We recently identified SPPL2A as the enzyme controlling turnover and functions of the invariant chain (CD74) of the major histocompatibility complex II (MHCII) and demonstrated critical importance of this process for B cell development. Surprisingly, we found that SPPL2A is critical for formation of dental enamel. In Sppl2a knockout mice, enamel of the erupted incisors was chalky white and rapidly eroded after eruption. SPPL2A was found to be expressed in enamel epithelium during secretory and maturation stage amelogenesis. Mineral content of enamel in Sppl2a⁻/⁻ incisors was inhomogeneous and reduced by ∼20% compared to wild-type mice with the most pronounced reduction at the mesial side. Frequently, disruption of the enamel layer and localized detachment of the most superficial enamel layer was observed in the knockout incisors leading to an uneven enamel surface. In Sppl2a null mice, morphology and function of secretory stage ameloblasts were not noticeably different from that of wild-type mice. However, maturation stage ameloblasts showed reduced height and a characteristic undulation of the ameloblast layer with localized adherence of the cells to the outer enamel. This was reflected in a delayed and incomplete resorption of the proteinaceous enamel matrix. Thus, we conclude that intramembrane proteolysis by SPPL2A is essential for maintaining cellular homeostasis of ameloblasts. Because modulation of SPPL2A activity appears to be an attractive therapeutic target to deplete B cells and treat autoimmunity, interference with tooth enamel formation should be investigated as a possible adverse effect of pharmacological SPPL2A inhibitors in humans.

Keyword(s): Ameloblasts: enzymology (MeSH) ; Animals (MeSH) ; Antigens, Differentiation, B-Lymphocyte: genetics (MeSH) ; Antigens, Differentiation, B-Lymphocyte: metabolism (MeSH) ; Aspartic Acid Endopeptidases: genetics (MeSH) ; Aspartic Acid Endopeptidases: metabolism (MeSH) ; Dental Enamel: enzymology (MeSH) ; Dental Enamel: growth & development (MeSH) ; Histocompatibility Antigens Class II: genetics (MeSH) ; Histocompatibility Antigens Class II: metabolism (MeSH) ; Incisor: enzymology (MeSH) ; Incisor: growth & development (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Proteolysis (MeSH) ; Antigens, Differentiation, B-Lymphocyte ; Histocompatibility Antigens Class II ; Membrane Proteins ; invariant chain ; Aspartic Acid Endopeptidases ; SPPL2a protein, mouse

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Contributing Institute(s):

1. Signal Peptide Peptidases as Models for γ-Secretase (AG Fluhrer)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2013

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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