Tuftelin1 Drives Experimental Pulmonary Fibrosis Progression by Facilitating Stress Fiber Assembly

Abstract

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts. However, the underlying mechanism of the disease remains elusive. This study was designed to evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis. Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro settings. Moreover, TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and N-WASP observed during microfilament formation. Meanwhile TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the Neuronal Wiskott-Aldrich syndrome protein (pY256N-WASP). Furthermore, TUFT1 promoted TGF-β1 induced fibroblast activation by increasing nuclear translocation of pY256N-WASP in fibroblasts, while wiskostatin, a N-WASP inhibitor, suppressed these processes. Our findings suggested TUFT1 plays an important role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.