TGFβ instructs mTORC2 to activate PKCβII for increased TWIST1 expression in proximal tubular epithelial cell injury

Falguni Das, Nandini Ghosh-choudhury, Soumya Maity, Balakuntalam S Kasinath, Goutam Ghosh Choudhury

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The plasticity of proximal tubular epithelial cells in response to TGFβ contributes to the expression of TWIST1 to drive renal fibrosis. The mechanism of TWIST1 expression is not known. We show that both PI3 kinase and its target mTORC2 increase TGFβ-induced TWIST1 expression. TGFβ enhances phosphorylation on Ser-660 in the protein kinase C βII (PKCβII) hydrophobic motif site. Remarkably, phosphorylation-deficient PKCβIIS660A, kinase-dead PKCβII, and PKCβII knockdown blocked TWIST1 expression by TGFβ. Inhibition of TWIST1 arrested TGFβ-induced tubular cell hypertrophy and the expression of fibronectin, collagen I (α2), and α-smooth muscle actin. By contrast, TWIST1 overexpression induced these pathologies. Interestingly, the inhibition of PKCβII reduced these phenomena, which were countered by the expression of TWIST1. These results provide the first evidence for the involvement of the mTORC2–PKCβII axis in TWIST1 expression to promote tubular cell pathology.

Original languageEnglish (US)
Pages (from-to)1300-1316
Number of pages17
JournalFEBS Letters
Volume597
Issue number9
DOIs
StatePublished - May 2023

Keywords

  • TWIST1
  • kidney fibrosis
  • matrix protein expansion
  • protein kinase C
  • transforming growth factor-β

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biophysics
  • Structural Biology
  • Biochemistry
  • Cell Biology

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