Oncoprotein DJ-1 interacts with mTOR complexes to effect transcription factor Hif1α-dependent expression of collagen I (α2) during renal fibrosis.
J Biol Chem
; 298(9): 102246, 2022 09.
Article
em En
| MEDLINE
| ID: mdl-35835217
ABSTRACT
Proximal tubular epithelial cells respond to transforming growth factor ß (TGFß) to synthesize collagen I (α2) during renal fibrosis. The oncoprotein DJ-1 has previously been shown to promote tumorigenesis and prevent apoptosis of dopaminergic neurons; however, its role in fibrosis signaling is unclear. Here, we show TGFß-stimulation increased expression of DJ-1, which promoted noncanonical mTORC1 and mTORC2 activities. We show DJ-1 augmented the phosphorylation/activation of PKCßII, a direct substrate of mTORC2. In addition, coimmunoprecipitation experiments revealed association of DJ-1 with Raptor and Rictor, exclusive subunits of mTORC1 and mTORC2, respectively, as well as with mTOR kinase. Interestingly, siRNAs against DJ-1 blocked TGFß-stimulated expression of collagen I (α2), while expression of DJ-1 increased expression of this protein. In addition, expression of dominant negative PKCßII and siRNAs against PKCßII significantly inhibited TGFß-induced collagen I (α2) expression. In fact, constitutively active PKCßII abrogated the effect of siRNAs against DJ-1, suggesting a role of PKCßII downstream of this oncoprotein. Moreover, we demonstrate expression of collagen I (α2) stimulated by DJ-1 and its target PKCßII is dependent on the transcription factor hypoxia-inducible factor 1α (Hif1α). Finally, we show in the renal cortex of diabetic rats that increased TGFß was associated with enhanced expression of DJ-1 and activation of mTOR and PKCßII, concomitant with increased Hif1α and collagen I (α2). Overall, we identified that DJ-1 affects TGFß-induced expression of collagen I (α2) via an mTOR-, PKCßII-, and Hif1α-dependent mechanism to regulate renal fibrosis.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Oncogênicas
/
Colágeno Tipo I
/
Diabetes Mellitus Experimental
/
Nefropatias Diabéticas
/
Subunidade alfa do Fator 1 Induzível por Hipóxia
/
Proteína Desglicase DJ-1
/
Alvo Mecanístico do Complexo 1 de Rapamicina
/
Alvo Mecanístico do Complexo 2 de Rapamicina
/
Rim
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos