The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90

Nat Immunol. 2013 Jan;14(1):72-81. doi: 10.1038/ni.2479. Epub 2012 Dec 2.

Abstract

Act1 is an essential adaptor in interleukin 17 (IL-17)-mediated signaling and is recruited to the receptor for IL-17 after stimulation with IL-17. Here we found that Act1 was a 'client' protein of the molecular chaperone hsp90. The D10N variant of Act1 (Act1(D10N)) that is linked to susceptibility to psoriasis was defective in its interaction with hsp90, which resulted in a global loss of Act1 function. Act1-deficient mice modeled the mechanistic link between loss of Act1 function and susceptibility to psoriasis. Although Act1 was necessary for IL-17-mediated inflammation, Act1-deficient mice had a hyperactive response of the T(H)17 subset of helper T cells and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17 signaling, IL-22 was the main contributor to skin inflammation, which provides a molecular mechanism for the association of Act1(D10N) with psoriasis susceptibility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Connexin 43 / genetics
  • Connexin 43 / immunology
  • Connexin 43 / metabolism*
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation / genetics
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism*
  • Polymorphism, Genetic
  • Protein Binding / genetics
  • Protein Binding / immunology
  • Psoriasis / genetics
  • Psoriasis / immunology*
  • Signal Transduction
  • Th17 Cells / immunology*

Substances

  • ACT1 protein
  • Connexin 43
  • HSP90 Heat-Shock Proteins
  • Interleukin-17
  • Molecular Chaperones
  • Peptide Fragments