Stimulation of Fibronectin Matrix Assembly by Lysine Acetylation.

TitleStimulation of Fibronectin Matrix Assembly by Lysine Acetylation.
Publication TypeJournal Article
Year of Publication2020
AuthorsVega, ME, Kastberger, B, Wehrle-Haller, B, Schwarzbauer, JE
Date Published2020 Mar 08
KeywordsAcetylation, Animals, Diabetic Nephropathies, Extracellular Matrix, Fibronectins, Humans, Lysine, Mice

<p>Diabetic nephropathy, a devastating consequence of diabetes mellitus, is characterized by the accumulation of extracellular matrix (ECM) that disrupts the kidney's filtration apparatus. Elevated glucose levels increase the deposition of a fibronectin (FN) matrix by mesangial cells, the primary matrix-producing cells of the kidney, and also increase acetyl-CoA leading to higher levels of lysine acetylation. Here, we investigated the connection between acetylation and the ECM and show that treatment of mesangial cells with deacetylase inhibitors increases both acetylation and FN matrix assembly compared to untreated cells. The matrix effects were linked to lysine 794 (K794) in the β1 integrin cytoplasmic domain based on studies of cells expressing acetylated (K794Q) and non-acetylated (K794R) mimetics. β1(K794Q) cells assembled significantly more FN matrix than wildtype β1 cells, while the non-acetylated β1(K794R) form was inactive. We show that mutation of K794 affects FN assembly by stimulating integrin-FN binding activity and cell contractility. Wildtype and β1(K794Q) cells but not β1(K794R) cells further increased their FN matrix when stimulated with deacetylase inhibitors indicating that increased acetylation on other proteins is required for maximum FN assembly. Thus, lysine acetylation provides a mechanism for glucose-induced fibrosis by up-regulation of FN matrix assembly.</p>

Alternate JournalCells
PubMed ID32182705
PubMed Central IDPMC7140634
Grant ListR01 AR073236 / AR / NIAMS NIH HHS / United States
F32 DK109622 / DK / NIDDK NIH HHS / United States