Palmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating β-catenin palmitoylation

Mengru Gu, Hanlu Jiang, Mengzhu Tan, Long Yu, Ning Xu, Ying Li, Han Wu, Qing Hou and Chunsun Dai ()
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Mengru Gu: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Hanlu Jiang: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Mengzhu Tan: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Long Yu: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Ning Xu: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Ying Li: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Han Wu: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Qing Hou: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China
Chunsun Dai: the Second Affiliated Hospital of Nanjing Medical University; Nanjing, China

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract palmitoylation, a reversible post-translational modification, is initiated by the DHHC family of palmitoyltransferases and reversed by several acyl protein thioesterases. However, the role and mechanisms for protein palmitoylation in renal fibrosis have not been elucidated. Here we show protein palmitoylation and DHHC9 were downregulated in the fibrotic kidneys of mouse models and chronic kidney disease (CKD) patients. Ablating DHHC9 in tubular cells aggravated, while inducing DHHC9 overexpression with adeno-DHHC9 transfection or iproniazid treatment protected against kidney fibrosis in male mouse models. Mechanistically, DHHC9 palmitoylated β-catenin, thereby promoted its ubiquitination and degradation. Additionally, acyl protein thioesterase 1 (APT1) was induced in the fibrotic kidneys, which depalmitoylated β-catenin, increased its abundance and nuclear translocation. Ablating tubular APT1 or inhibiting APT1 with ML348 markedly protected against unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI)-induced kidney fibrosis in male mice. This study reveals the regulatory mechanism of protein palmitoylation in kidney fibrosis.

Date: 2023
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DOI: 10.1038/s41467-023-42476-z

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