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

Journal of immunology (Baltimore, Md. : 1950) 2019 Mar 01

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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. Copyright © 2019 by The American Association of Immunologists, Inc.

Citation

Katarzyna Bulek, Xing Chen, Vandy Parron, Aparna Sundaram, Tomasz Herjan, Suidong Ouyang, Caini Liu, Alana Majors, Jarod Zepp, Ji Gao, Ashok Dongre, Malgorzata Bodaszewska-Lubas, Arnaud Echard, Mark Aronica, Julie Carman, Stavros Garantziotis, Dean Sheppard, Xiaoxia Li. IL-17A Recruits Rab35 to IL-17R to Mediate PKCα-Dependent Stress Fiber Formation and Airway Smooth Muscle Contractility. Journal of immunology (Baltimore, Md. : 1950). 2019 Mar 01;202(5):1540-1548