BRIEF RESEARCH REPORT article
Front. Cell Dev. Biol.
Sec. Signaling
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1637770
This article is part of the Research TopicDeciphering Signaling Pathway Interactions in Tissue HomeostasisView all 4 articles
The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation
Provisionally accepted
- Pennington Biomedical Research Center, Baton Rouge, United States
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The malate-aspartate shuttle (MAS) is a key biochemical system that facilitates the transfer of reducing equivalents from the cytosol into mitochondria. It consists of two pairs of cytosolic and mitochondrial enzymes: glutamic-oxaloacetic transaminases (cGOT1, mGOT2) and malate dehydrogenases (cMDH1, mMDH2). We recently reported that cytosolic GOT1 is selectively elevated in brown adipocytes during cold exposure, while the expression of other MAS enzymes remains unchanged. Mechanistically, cold-induced activation of the β-adrenergic receptor (βAR)-cAMP-PKA signaling pathway promotes Got1 transcription through the transcriptional coactivators PGC-1α and NT-PGC-1α. The resulting increase in GOT1 levels activates the MAS, thereby supporting mitochondrial respiration through enhanced fatty acid oxidation. In the present study, we identify the βAR-SGK1 (Serum-and Glucocorticoid-inducible Kinase 1) signaling axis as a novel regulatory mechanism that maintains GOT1 protein stability. SGK1 is activated downstream of βAR signaling in brown adipocytes during cold exposure. We show that expression of SGK1 S422D , a constitutively active form of SGK1, protects GOT1 from ubiquitination by the E3 ubiquitin ligase RNF34 and subsequent degradation by the proteasome.Conversely, both pharmacological and genetic inhibition of SGK1 during βAR stimulation leads to a reduction in GOT1 protein levels without altering its mRNA expression. Together, these findings uncover a previously unrecognized role for the βAR-SGK1 signaling pathway in maintaining GOT1 protein stability in brown adipocytes, highlighting a multilayered signaling network that orchestrates metabolic adaptation during cold-induced activation.
Keywords: beta-adrenergic receptor, SGK1, GOT1, Brown adipose tissue (BAT), Malate-aspartate shuttle (MAS), signaling / signaling pathways, Ubiquitin-poteasome system
Received: 29 May 2025; Accepted: 08 Jul 2025.
Copyright: © 2025 Park, Park, Collier and Chang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ji Suk Chang, Pennington Biomedical Research Center, Baton Rouge, United States
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