Background: Kidney fibrosis, the excessive accumulation and dysregulated remodeling of the extracellular matrix, is the principal pathophysiological process in chronic kidney disease (CKD). Protein L-isoaspartyl/D-aspartyl methyltransferase (PCMT1) is crucial in repairing post-translational modifications of L-isoaspartyl residues, which are important for extracellular matrix proteins because of their low turnover rate and susceptibility to accelerating factors. This study aimed to reveal a novel role of PCMT1 in kidney fibrosis.
Methods: Kidney tissues from mice and humans were evaluated for PCMT1 expression and its association with fibrosis and kidney function. PCMT1's effects on the TGF-β1/Smad signaling were analyzed, and its functional role was assessed in tubule-specific Pcmt1 knockout murine models of kidney fibrosis. The ability of secreted PCMT1 to repair L-isoaspartyl residues on the ectodomain of transforming growth factor beta receptor 2 (TGFBR2) was investigated through immunoprecipitation, gene lentivirus overexpression or knockout, and post-translational modification mass spectrometry.
Results: PCMT1 expression was decreased in the tubules of human kidney biopsies from patients with CKD and murine fibrosis models. Renal tubule-specific PCMT1 deficiency in murine kidney fibrosis models worsened tubular injury, extracellular matrix protein deposition, myofibroblast activation, and TGF-β1/Smad signaling overactivation. Mechanistically, PCMT1 was unconventionally secreted and enzymatically inhibited TGF-β1-induced extracellular matrix protein deposition in vitro. PCMT1 interacted with TGFBR2, reversing N63 deamination on its ectodomain, which triggered TGFBR2 ubiquitination and degradation. PCMT1 supplementation in kidneys decreased TGFBR2 levels, attenuated TGF-β1/Smad overactivation, and impeded the profibrotic process.
Conclusions: Our study highlights the importance of PCMT1 in maintaining extracellular matrix homeostasis and mitigating kidney fibrosis by regulating TGFBR2 deamination and its protein stability, suppressing the TGF-β1/Smad signaling.
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