TGFβ1-Smad3 signaling mediates the formation of a stable serine racemase dimer in microglia

d-serine is synthesized by serine racemase (SR), a fold type II class of pyridoxal-5′-phosphate (PLP)-dependent enzyme. Whereas X-ray crystallography reveals that SR can be monomeric, reversible dimers having the highest racemase activity, or stable SR dimers resistant to both denaturation and reduc...

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Published in:Biochimica et biophysica acta. Proteins and proteomics 2020-09, Vol.1868 (9), p.140447-140447, Article 140447
Main Authors: Beltrán-Castillo, Sebastián, Triviño, Juan José, Eugenín, Jaime, von Bernhardi, Rommy
Format: Article
Language:English
Subjects:
Glial cells
Neuroinflammation
Serine racemase
Transforming growth factor β1
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Summary:d-serine is synthesized by serine racemase (SR), a fold type II class of pyridoxal-5′-phosphate (PLP)-dependent enzyme. Whereas X-ray crystallography reveals that SR can be monomeric, reversible dimers having the highest racemase activity, or stable SR dimers resistant to both denaturation and reductive treatment, showing reduced racemase activity have been detected in microglia and astrocytes; the latter especially in oxidative or inflammatory environments. The microglial inflammatory environment depends largely on the TGFβ1-mediated regulation of inflammatory cytokines such as TNFα and IL1β. Here we evaluated the participation of TGFβ1 in the regulation of SR, and whether that regulation is associated with the induction of stable SR dimers in the microglia from adult mice. In contrast to the effect of lipopolysaccharide (LPS), TGFβ1 increased the formation of stable SR dimers and reduced the detection of monomers in microglia in culture. LPS or TGFβ1 did not change the amount of total SR. The increase of stable SR dimer was abolished when TGFβ1 treatment was done in the presence of the Smad inhibitor SIS3, showing that Smad3 has a role in the induction of stable dimers. Treatment with TGFβ1 + SIS3 also reduced total SR, indicating that the canonical TGFβ1 pathway participates in the regulation of the synthesis or degradation of SR. In addition, the decrease of IL1β, but not the decrease of TNFα induced by TGFβ1, was mediated by Smad3. Our results reveal a mechanism for the regulation of d-serine through the induction of stable SR dimers mediated by TGFβ1-Smad3 signaling in microglia. •Low activity stable serine racemase dimers are induced by TGFβ1-Smad3 in microglia.•Inhibition of the Smad-dependent TGFβ1 signaling reduces total serine racemase.•Lipopolysaccharide and SIS3 increase the high activity monomeric Serine Racemase.•Smad-dependent TGFβ1 signaling reduces IL1β but not TNFα in adult mice microglia.•TGFβ1 contributes to avoid d-serine and NMDAR mediated glutamate excitotoxicity.
ISSN:1570-9639
1878-1454
DOI:10.1016/j.bbapap.2020.140447