TY - JOUR
T1 - TGFβ instructs mTORC2 to activate PKCβII for increased TWIST1 expression in proximal tubular epithelial cell injury
AU - Das, Falguni
AU - Ghosh-choudhury, Nandini
AU - Maity, Soumya
AU - Kasinath, Balakuntalam S
AU - Ghosh Choudhury, Goutam
N1 - Publisher Copyright:
© 2023 Federation of European Biochemical Societies.
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
KW - TWIST1
KW - kidney fibrosis
KW - matrix protein expansion
KW - protein kinase C
KW - transforming growth factor-β
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U2 - 10.1002/1873-3468.14599
DO - 10.1002/1873-3468.14599
M3 - Article
C2 - 36775967
AN - SCOPUS:85148416419
SN - 0014-5793
VL - 597
SP - 1300
EP - 1316
JO - FEBS Letters
JF - FEBS Letters
IS - 9
ER -