Rbms1 promotes pulmonary fibrosis by stabilising Sumo2 mRNA to facilitate Smad4-SUMOylation and fibroblast activation.

Abstract

The formation of myofibroblast foci constitutes a hallmark pathological feature of idiopathic pulmonary fibrosis (IPF), yet the mechanism remains elusive. RNA binding motif single-stranded interacting protein 1 (RBMS1), is known to be essential for proliferation and cell cycle progression; however, its role in pulmonary fibrosis remains to be clarified.This study aimed to systematically elucidate the role and underlying mechanism of RBMS1 in pulmonary fibrosis utilising mouse primary lung fibroblasts (mPLFs), fibroblast-specific Rbms1 deletion and overexpression mice models, and lung samples from IPF patients.RBMS1 was highly expressed in both IPF patient lungs and murine bleomycin (BLM)-induced fibrotic lesions. Notably, elevated RBMS1 expression was observed in the cytoplasm of mPLFs following TGF-β1 stimulation. Rbms1 promoted lung fibroblast activation, while knockdown of Rbms1 mitigated TGF-β1-induced fibrogenesis. In vivo, overexpression impaired lung function and exacerbated pulmonary fibrosis, whereas fibroblast-specific Rbms1 deletion exhibited a significant reduction in fibrosis post-BLM treatment. Mechanistically, Rbms1 binds to Sumo2 3'UTR, enhancing the mRNA stability. Furthermore, Rbms1 induced the SUMOylation of Smad4, with lysine 158 identified as a critical SUMOylation site. Meanwhile, Sumo2 knockdown alleviated the Rbms1-driven exacerbation of pulmonary fibrosis. Importantly, the nortriptyline pharmacologically inhibited RBMS1 to ameliorate pulmonary fibrosis in mice.Collectively, our study sheds light on the regulatory role of RBMS1 in pulmonary fibrosis, highlighting its therapeutic potential for targeted antifibrotic strategies.