Trophic factor BDNF inhibits GABAergic signaling by facilitating dendritic enrichment of SUMO E3 ligase PIAS3 and altering gephyrin scaffold.

Autor:	Thirouin ZS; Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland., Figueiredo M; Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland., Hleihil M; Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland., Gill R; Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada., Bosshard G; Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland., McKinney RA; Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada., Tyagarajan SK; Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland. Electronic address: tyagarajan@pharma.uzh.ch.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 May; Vol. 298 (5), pp. 101840. Date of Electronic Publication: 2022 Mar 17.
DOI:	10.1016/j.jbc.2022.101840
Abstrakt:	Posttranslational addition of a small ubiquitin-like modifier (SUMO) moiety (SUMOylation) has been implicated in pathologies such as brain ischemia, diabetic peripheral neuropathy, and neurodegeneration. However, nuclear enrichment of SUMO pathway proteins has made it difficult to ascertain how ion channels, proteins that are typically localized to and function at the plasma membrane, and mitochondria are SUMOylated. Here, we report that the trophic factor, brain-derived neurotrophic factor (BDNF) regulates SUMO proteins both spatially and temporally in neurons. We show that BDNF signaling via the receptor tropomyosin-related kinase B facilitates nuclear exodus of SUMO proteins and subsequent enrichment within dendrites. Of the various SUMO E3 ligases, we found that PIAS-3 dendrite enrichment in response to BDNF signaling specifically modulates subsequent ERK1/2 kinase pathway signaling. In addition, we found the PIAS-3 RING and Ser/Thr domains, albeit in opposing manners, functionally inhibit GABA-mediated inhibition. Finally, using oxygen-glucose deprivation as an in vitro model for ischemia, we show that BDNF-tropomyosin-related kinase B signaling negatively impairs clustering of the main scaffolding protein at GABAergic postsynapse, gephyrin, whereby reducing GABAergic neurotransmission postischemia. SUMOylation-defective gephyrin K148R/K724R mutant transgene expression reversed these ischemia-induced changes in gephyrin cluster density. Taken together, these data suggest that BDNF signaling facilitates the temporal relocation of nuclear-enriched SUMO proteins to dendrites to influence postsynaptic protein SUMOylation. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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