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Fam20C‐mediated phosphorylation of osteopontin is critical for its secretion but dispensable for its action as a cytokine in the activation of hepatic stellate cells in liver fibrogenesis
Author(s) -
Tibaldi Elena,
Brocca Alessandra,
Sticca Antonietta,
Gola Elisabetta,
Pizzi Marco,
Bordin Luciana,
Pagano Mario Angelo,
Mazzorana Marco,
Donà Gabriella,
Violi Paola,
Marin Oriano,
Romano Antonella,
Angeli Paolo,
Carraro Amedeo,
Brunati Anna Maria
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900880r
Subject(s) - osteopontin , hepatic stellate cell , phosphorylation , microbiology and biotechnology , chemistry , secretion , extracellular matrix , biology , endocrinology , biochemistry
Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and in cultured activated hepatic stellate cells (HSCs), we show that OPN, besides being overexpressed, is substantially phosphorylated by family with sequence similarity 20, member C (Fam20C), formerly known as Golgi casein kinase (G‐CK), which is exclusively resident in the Golgi apparatus. In both experimental models, Fam20C becomes overactive when associated with a 500‐kDa multiprotein complex, as compared with the negligible activity in livers of sham‐operated rats and in quiescent HSCs. Fam20C knockdown not only confirmed the role of Fam20C itself in OPN phosphorylation, but also revealed that phosphorylation was essential for OPN secretion. However, OPN acts as a fibrogenic factor independently of its phosphorylation state, as demonstrated by the increased expression of Collagen‐I by HSCs incubated with either a phosphorylated or nonphosphorylated form of recombinant OPN. Collectively, our results confirm that OPN promotes liver fibrosis and highlight Fam20C as a novel factor driving this process by favoring OPN secretion from HSCs, opening new avenues for deciphering yet unidentified mechanisms underlying liver fibrogenesis.