Human antigen R promotes lung fibroblast differentiation to myofibroblasts and increases extracellular matrix production. Issue 10 (14th April 2021)

• Record Type: Journal Article
• Authors: Al‐Habeeb, Fatmah; Aloufi, Noof; Traboulsi, Hussein; Liu, Xingxing; Nair, Parameswaran; Haston, Christina; Azuelos, Ilan; Huang, Steven K.; White, Eric S.; Gallouzi, Imed E.; Di Marco, Sergio; Eidelman, David H.; Baglole, Carolyn J.
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 10(2021)
• Page Start: 6836
• Page End: 6851
• Publication Date: 2021-04-14
• Subjects: bleomycin -- collagen -- ELAVL1 -- human antigen R -- idiopathic pulmonary fibrosis -- radiation -- α‐smooth muscle actin; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30380
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Idiopathic pulmonary fibrosis (IPF) is a disease of progressive scarring caused by excessive extracellular matrix (ECM) deposition and activation of α‐SMA‐expressing myofibroblasts. Human antigen R (HuR) is an RNA binding protein that promotes protein translation. Upon translocation from the nucleus to the cytoplasm, HuR functions to stabilize messenger RNA (mRNA) to increase protein levels. However, the role of HuR in promoting ECM production, myofibroblast differentiation, and lung fibrosis is unknown. Human lung fibroblasts (HLFs) treated with transforming growth factor β1 (TGF‐β1) showed a significant increase in translocation of HuR from the nucleus to the cytoplasm. TGF‐β‐treated HLFs that were transfected with HuR small interfering RNA had a significant reduction in α‐SMA protein as well as the ECM proteins COL1A1, COL3A, and FN1. HuR was also bound to mRNA for ACTA2, COL1A1, COL3A1, and FN . HuR knockdown affected the mRNA stability of ACTA2 but not that of the ECM genes COL1A1, COL3A1, or FN . In mouse models of pulmonary fibrosis, there was higher cytoplasmic HuR in lung structural cells compared to control mice. In human IPF lungs, there was also more cytoplasmic HuR. This study is the first to show that HuR in lung fibroblasts controls their differentiation to myofibroblasts and consequent ECM production. Further research on HuR could assist in establishing the basis for the development of new target therapy for fibrotic diseases, such as IPF. Abstract : Human antigen R (HuR) is an RNA‐binding protein whose involvement in lung fibrosis is not known. We show that HuR is required for transforming growth factor‐β‐induced lung fibroblast differentiation to myofibroblasts and extracellular matrix protein production. Mouse models of lung fibrosis and human IPF lungs have increased cytoplasmic HuR in lung cells, a feature that is indicative of its activation. Together, these data highlight the involvement of HuR in the pathogenesis of pulmonary fibrosis.