Latency-Associated Peptide Rapidly Upregulates Neuraminidase 3 in a Profibrotic Translation-Based Positive Feedback...

Area of Science:

• Cell Biology
• Molecular Biology
• Pathology

Background:

• Fibrosis is a pathological scarring process driven by dysregulated wound healing.
• Transforming growth factor beta-1 (TGF-β1) is a key cytokine implicated in fibrosis.
• Neuraminidase 3 (NEU3) is upregulated by TGF-β1 and activates latent TGF-β1, suggesting a feedback loop.

Purpose of the Study:

• To investigate the rapid regulation of NEU3 by TGF-β1 in human lung fibroblasts.
• To elucidate the role of NEU3 in a positive feedback loop involving TGF-β1 and latency-associated peptide (LAP).
• To identify molecular mediators of NEU3 regulation and their potential as therapeutic targets.

Main Methods:

• Primary human lung fibroblasts were treated with TGF-β1 and LAP.
• NEU3 protein and mRNA levels were assessed using Western blotting and RT-qPCR.
• Translation and transcription were evaluated.
• The role of DEAD-box helicase 3 (DDX3) and its inhibitor RK-33 were investigated.

Main Results:

• TGF-β1 rapidly increased intracellular and extracellular NEU3 protein levels within 5 minutes via enhanced translation, independent of new transcription.
• LAP synergistically upregulated NEU3 with TGF-β1.
• NEU3 inhibitors and the DDX3 inhibitor RK-33 blocked the TGF-β1- and LAP-induced NEU3 upregulation.
• TGF-β1, but not LAP, induced DDX3 dephosphorylation.

Conclusions:

• A rapid positive feedback loop involving TGF-β1, LAP, and NEU3, mediated by DDX3-dependent translation, contributes to the pathogenesis of fibrosis.
• Targeting NEU3 or DDX3 may offer therapeutic strategies for fibrotic diseases.