Neuraminidase 3 acts in a rapid translation-based positive feedback loop to activate TGF-β1

Fibrosis appears to be an out-of-control wound healing response that drives a progressive formation of scar tissue in an organ. A key profibrotic cytokine, transforming growth factor beta-1 (TGF-{beta}1), upregulates levels of the fibrosis-driving sialidase, neuraminidase 3 (NEU3), and NEU3 can activate latent TGF-{beta}1 to release active TGF-{beta}1 from the sequestering LAP peptide. In the mouse bleomycin model of pulmonary fibrosis, NEU3 is both necessary and sufficient for fibrosis. In this report, we find that NEU3 levels increase both intracellularly and extracellularly in cultures of human lung fibroblasts within 5 minutes of TGF-{beta}1 exposure. This effect is driven by an increase in translation and is independent of new transcription, supporting a model where TGF-{beta}1 causes a pool of weakly translated NEU3 mRNA to increase translation. The RNA helicase DEAD-box helicase 3 (DDX3) mediates NEU3 translation. TGF-{beta}1 induces dephosphorylation of DDX3 within two minutes, and DDX3 inhibitors block the rapid NEU3 upregulation. The NEU3-TGF-{beta}1-NEU3 positive feedback loop is activated within 5 minutes, and the remaining LAP fragment (after NEU3 activation of the latent TGF-{beta}1 complex) appears to potentiate NEU3 upregulation. This feedback loop is blocked by NEU3 inhibitors. These findings suggest that NEU3 is a rapidly acting amplifier of TGF-{beta}1 signaling, likely through TGF-{beta}1-mediated dephosphorylation of DDX3, and this mechanism may be associated with an early tissue-healing response mechanism that drives the initiation and progression of fibrosis.