Alternative Polyadenylation Contributes to Fibroblast Senescence in Pulmonary Fibrosis

ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age‐related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence‐associated secretory phenotype (SASP) turns senescent fibroblasts into pro‐inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post‐transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA‐binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) tail at different sites of 3′ UTR and generates transcript isoforms with different 3′ UTR lengths. We found that NUDT21 was downregulated in aging and fibrotic lungs, particularly at the fibrotic foci of IPF lungs known to have abundant senescent myofibroblasts and collagens. NUDT21 knockdown in normal lung fibroblasts promoted the 3′ UTR shortening of several STAT3 signaling components and enhanced STAT3 phosphorylation and the expression of several SASPs, including interleukins, collagens, and matrix metalloproteinases (MMPs). Moreover, NUDT21 downregulation may be associated with increased fibroblast senescence and abnormal mitochondrial function. Importantly, mice with Nudt21 deletion in Col1a1 expressing cells aggravated bleomycin‐induced pulmonary fibrosis. Taking together, our study demonstrated an important role of NUDT21‐mediated APA in regulating SASP expression and fibroblast senescence that could contribute to the pathogenesis of IPF.