Corneal antifibrotic switch identified in genetic and pharmacological deficiency of vimentin Article

Bargagna-Mohan, P, Paranthan, RR, Hamza, A et al. (2012). Corneal antifibrotic switch identified in genetic and pharmacological deficiency of vimentin . JOURNAL OF BIOLOGICAL CHEMISTRY, 287(2), 989-1006. 10.1074/jbc.M111.297150

cited authors

  • Bargagna-Mohan, P; Paranthan, RR; Hamza, A; Zhan, CG; Lee, DM; Kim, KB; Lau, DL; Srinivasan, C; Nakayama, K; Nakayama, KI; Herrmann, H; Mohan, R



  • The type III intermediate filaments (IFs) are essential cytoskeletal elements of mechanosignal transduction and serve critical roles in tissue repair. Mice genetically deficient for the IF protein vimentin (Vim -/-) have impaired wound healing from deficits in myofibroblast development. We report a surprising finding made in Vim-/- mice that corneas are protected from fibrosis and instead promote regenerative healing after traumatic alkali injury. This reparative phenotype in Vim-/- corneas is strikingly recapitulated by the pharmacological agent withaferin A (WFA), a small molecule that binds to vimentin and down-regulates its injury-induced expression. Attenuation of corneal fibrosis by WFA is mediated by down-regulation of ubiquitin-conjugating E3 ligase Skp2 and up-regulation of cyclin-dependent kinase inhibitors p27Kip1 and p21Cip1. In cell culture models, WFA exerts G2/M cell cycle arrest in a p27 Kip1- and Skp2-dependent manner. Finally, by developing a highly sensitive imaging method to measure corneal opacity, we identify a novel role for desmin overexpression in corneal haze. We demonstrate that desmin down-regulation by WFA via targeting the conserved WFA-ligand binding site shared among type III IFs promotes further improvement of corneal transparency without affecting cyclin-dependent kinase inhibitor levels in Vim-/- mice. This dissociates a direct role for desmin in corneal cell proliferation. Taken together, our findings illuminate a previously unappreciated pathogenic role for type III IF overexpression in corneal fibrotic conditions and also validate WFA as a powerful drug lead toward anti-fibrosis therapeutic development. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

publication date

  • January 6, 2012

published in

Digital Object Identifier (DOI)

start page

  • 989

end page

  • 1006


  • 287


  • 2