The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation
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...
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Frontiers Media S.A.
2025-07-01
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| author | Chul-Hong Park Minsung Park J. Jason Collier Ji Suk Chang |
| author_facet | Chul-Hong Park Minsung Park J. Jason Collier Ji Suk Chang |
| author_sort | Chul-Hong Park |
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| description | 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 SGK1S422D, 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. |
| format | Article |
| id | doaj-art-dbe1572f7edb4aebb414591c057d4d8b |
| institution | Kabale University |
| issn | 2296-634X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-dbe1572f7edb4aebb414591c057d4d8b2025-08-20T03:50:53ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2025-07-011310.3389/fcell.2025.16377701637770The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradationChul-Hong Park0Minsung Park1J. Jason Collier2Ji Suk Chang3Laboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, United StatesLaboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, United StatesIslet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA, United StatesLaboratory of Gene Regulation and Metabolism, Pennington Biomedical Research Center, Baton Rouge, LA, United StatesThe 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 SGK1S422D, 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.https://www.frontiersin.org/articles/10.3389/fcell.2025.1637770/fullbeta-adrenergic receptorSGK1GOT1Brown adipose tissue (BAT)malate-aspartate shuttle (MAS)signaling/signaling pathways |
| spellingShingle | Chul-Hong Park Minsung Park J. Jason Collier Ji Suk Chang The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation Frontiers in Cell and Developmental Biology beta-adrenergic receptor SGK1 GOT1 Brown adipose tissue (BAT) malate-aspartate shuttle (MAS) signaling/signaling pathways |
| title | The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation |
| title_full | The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation |
| title_fullStr | The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation |
| title_full_unstemmed | The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation |
| title_short | The β-adrenergic receptor-SGK1 signaling pathway in brown adipocytes protects GOT1 from proteasomal degradation |
| title_sort | β adrenergic receptor sgk1 signaling pathway in brown adipocytes protects got1 from proteasomal degradation |
| topic | beta-adrenergic receptor SGK1 GOT1 Brown adipose tissue (BAT) malate-aspartate shuttle (MAS) signaling/signaling pathways |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2025.1637770/full |
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