P311 Promotes Lung Fibrosis via Stimulation of Transforming Growth Factor-β1, -β2, and -β3 Translation

Am J Respir Cell Mol Biol. 2019 Feb;60(2):221-231. doi: 10.1165/rcmb.2018-0028OC.

Abstract

Interstitial lung fibrosis, a frequently idiopathic and fatal disease, has been linked to the increased expression of profibrotic transforming growth factor (TGF)-βs. P311 is an RNA-binding protein that stimulates TGF-β1, -β2, and -β3 translation in several cell types through its interaction with the eukaryotic translation initiation factor 3b. We report that P311 is switched on in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and in the mouse model of bleomycin (BLM)-induced pulmonary fibrosis. To assess the in vivo role of P311 in lung fibrosis, BLM was instilled into the lungs of P311-knockout mice, in which fibrotic changes were significantly decreased in tandem with a reduction in TGF-β1, -β2, and -β3 concentration/activity compared with BLM-treated wild-type mice. Complementing these findings, forced P311 expression increased TGF-β concentration/activity in mouse and human lung fibroblasts, thereby leading to an activated phenotype with increased collagen production, as seen in IPF. Consistent with a specific effect of P311 on TGF-β translation, TGF-β1-, -β2-, and -β3-neutralizing antibodies downregulated P311-induced collagen production by lung fibroblasts. Furthermore, treatment of BLM-exposed P311 knockouts with recombinant TGF-β1, -β2, and -β3 induced pulmonary fibrosis to a degree similar to that found in BLM-treated wild-type mice. These studies demonstrate the essential function of P311 in TGF-β-mediated lung fibrosis. Targeting P311 could prove efficacious in ameliorating the severity of IPF while circumventing the development of autoimmune complications and toxicities associated with the use of global TGF-β inhibitors.

Keywords: P311; bleomycin; fibroblasts; lung fibrosis; transforming growth factor-β.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bleomycin
  • Case-Control Studies
  • Collagen / genetics
  • Collagen / metabolism
  • Disease Models, Animal
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Humans
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Oncogene Proteins / metabolism*
  • Protein Biosynthesis
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / pathology*
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / metabolism
  • Transforming Growth Factor beta3 / genetics
  • Transforming Growth Factor beta3 / metabolism

Substances

  • NREP protein, human
  • Nerve Tissue Proteins
  • Oncogene Proteins
  • P311 protein, mouse
  • Tgfb2 protein, mouse
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • Transforming Growth Factor beta3
  • Bleomycin
  • Collagen