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IQGAP1 Mediates α-Smooth Muscle Actin Expression and Enhances Contractility of Lung Fibroblasts

Akter T, Atanelishvili I, Shirai Y, Garcia-Martos A, Silver RM and Bogatkevich GS

Contractility is a predominant feature of myofibroblasts and a key process in fibrotic tissue remodeling. We previously demonstrated that lung fibroblasts from scleroderma patients with interstitial lung disease express a robust contractile phenotype and contain large amounts of the IQ motif containing GTPase activating protein (IQGAP1). Here we show the contribution of IQGAP1 to two major features of lung myofibroblasts: α-smooth muscle actin (SMA) expression and collagen gel contraction. We found that IQGAP1 mediates SMA expression and contractile activity of scleroderma lung myofibroblasts as well as normal lung fibroblasts stimulated in vitro with thrombin, TGFβ1, or CTGF. We show that IQGAP1 co-immunoprecipitates with SMA and co-localizes with monomeric SMA, but not with the highly organized SMA in scleroderma lung myofibroblasts. In contrast, IQGAP1 binds directly to polymerized β- and γ-actin isoforms suggesting distinct mechanisms of α-SMA and β-/γ-actin polymerization in scleroderma lung myofibroblasts. We conclude that the primary role of IQGAP1 in promoting contractility of the lung parenchyma and contributing to restrictive lung disease is through the regulation of SMA expression and organization in lung fibroblasts.