β-catenin-inhibited Sumoylation modification of LKB1 and fatty acid metabolism is critical in renal fibrosis.
Sumoylation
Animals
beta Catenin
/ metabolism
Fibrosis
Humans
Fatty Acids
/ metabolism
Protein Serine-Threonine Kinases
/ metabolism
Mice
AMP-Activated Protein Kinase Kinases
Male
AMP-Activated Protein Kinases
/ metabolism
Kidney
/ pathology
Mice, Inbred C57BL
Kidney Diseases
/ metabolism
Small Ubiquitin-Related Modifier Proteins
/ metabolism
Signal Transduction
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
22 Oct 2024
22 Oct 2024
Historique:
received:
15
09
2023
accepted:
11
10
2024
revised:
09
10
2024
medline:
23
10
2024
pubmed:
23
10
2024
entrez:
22
10
2024
Statut:
epublish
Résumé
Liver kinase B1 (LKB1) is a serine/threonine kinase controlling cell homeostasis. Among post-translational modification, Sumoylation is vital for LKB1 activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), the key regulator in energy metabolism. Of note, AMPK-regulated fatty acid metabolism is highly involved in maintaining normal renal function. However, the regulative mechanisms of LKB1 Sumoylation remain elusive. In this study, we demonstrated that β-catenin, a notorious signal in renal fibrosis, inhibited the Sumoylation of LKB1, thereby disrupting fatty acid oxidation in renal tubular cells and triggering renal fibrosis. Mechanically, we found that Sumo3 was the key mediator for LKB1 Sumoylation in renal tubular cells, which was transcriptionally inhibited by β-catenin/Transcription factor 4 (TCF4) signaling. Overexpression of Sumo3, not Sumo1 or Sumo2, restored β-catenin-disrupted fatty acid metabolism, and retarded lipid accumulation and fibrogenesis in the kidney. In vivo, conditional knockout of β-catenin in tubular cells effectively preserved fatty acid oxidation and blocked lipid accumulation by maintaining LKB1 Sumoylation and AMPK activation. Furthermore, ectopic expression of Sumo3 strongly inhibited Wnt1-aggravated lipid accumulation and fibrogenesis in unilateral ischemia-reperfusion mice. In patients with chronic kidney disease, we found a loss of Sumo3 expression, and it was highly related to LKB1 repression. This contributes to fatty acid metabolism disruption and lipid accumulation, resulting in renal fibrosis. Overall, our study revealed a new mechanism in fatty acid metabolism dysfunction and provided a new therapeutic target pathway for regulating Sumo modification in renal fibrosis.
Identifiants
pubmed: 39438470
doi: 10.1038/s41419-024-07154-y
pii: 10.1038/s41419-024-07154-y
doi:
Substances chimiques
beta Catenin
0
Fatty Acids
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
AMP-Activated Protein Kinase Kinases
EC 2.7.11.3
STK11 protein, human
EC 2.7.11.1
AMP-Activated Protein Kinases
EC 2.7.11.31
Stk11 protein, mouse
EC 2.7.11.1
Small Ubiquitin-Related Modifier Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
769Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82225010
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82070707
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 81900627
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 82100786
Organisme : Natural Science Foundation of Guangxi Province (Guangxi Natural Science Foundation)
ID : 2021GXNSFAA196057
Informations de copyright
© 2024. The Author(s).
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