IL-17A Recruits Rab35 to IL-17R to Mediate PKCα-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility

J Immunol. 2019 Mar 1;202(5):1540-1548. doi: 10.4049/jimmunol.1801025. Epub 2019 Jan 25.


IL-17A is a critical proinflammatory cytokine for the pathogenesis of asthma including neutrophilic pulmonary inflammation and airway hyperresponsiveness. In this study, by cell type-specific deletion of IL-17R and adaptor Act1, we demonstrated that IL-17R/Act1 exerts a direct impact on the contraction of airway smooth muscle cells (ASMCs). Mechanistically, IL-17A induced the recruitment of Rab35 (a small monomeric GTPase) and DennD1C (guanine nucleotide exchange factor [GEF]) to the IL-17R/Act1 complex in ASMCs, resulting in activation of Rab35. Rab35 knockdown showed that IL-17A-induced Rab35 activation was essential for protein kinase Cα (PKCα) activation and phosphorylation of fascin at Ser39 in ASMCs, allowing F-actin to interact with myosin to form stress fibers and enhance the contraction induced by methacholine. PKCα inhibitor or Rab35 knockdown indeed substantially reduced IL-17A-induced stress fiber formation in ASMCs and attenuated IL-17A-enhanced, methacholine-induced contraction of airway smooth muscle. Taken together, these data indicate that IL-17A promotes airway smooth muscle contraction via direct recruitment of Rab35 to IL-17R, followed by PKCα activation and stress fiber formation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Interleukin-17 / antagonists & inhibitors
  • Interleukin-17 / deficiency
  • Interleukin-17 / metabolism*
  • Mice
  • Mice, Knockout
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism*
  • Protein Kinase C-alpha / antagonists & inhibitors*
  • Protein Kinase C-alpha / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Interleukin-17 / antagonists & inhibitors
  • Receptors, Interleukin-17 / metabolism*
  • Stress Fibers / drug effects
  • Stress Fibers / metabolism*
  • rab GTP-Binding Proteins / antagonists & inhibitors
  • rab GTP-Binding Proteins / metabolism*


  • Il17a protein, mouse
  • Interleukin-17
  • Protein Kinase Inhibitors
  • Receptors, Interleukin-17
  • Protein Kinase C-alpha
  • Rab35 protein, mouse
  • rab GTP-Binding Proteins