title: The intramembrane protease SPPL2A is critical for tooth enamel formation.
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.
authors: Department of Oral Cell Biology ACTA, University of Amsterdam, Amsterdam, The Netherlands.
authors: Antonius L J J
authors: AL
authors: Bronckers
authors: Nur
authors: N
authors: Gueneli
authors: Renate
authors: R
authors: Lüllmann-Rauch
authors: Janna
authors: J
authors: Schneppenheim
authors: Andreea P
authors: AP
authors: Moraru
authors: Nina
authors: N
authors: Himmerkus
authors: Theodore J
authors: TJ
authors: Bervoets
authors: Regina
authors: R
authors: Fluhrer
authors: Vincent
authors: V
authors: Everts
authors: Paul
authors: P
authors: Saftig
authors: Bernd
authors: B
authors: Schröder
mesh_terms: D000565:Ameloblasts / Q000201:enzymology*; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003743:Dental Enamel / Q000201:enzymology* / Q000254:growth & development; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D007180:Incisor / Q000201:enzymology* / Q000254:growth & development; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008565:Membrane Proteins; C045084:invariant chain; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse