Chinese cobra (Naja atra) SVPLA₂ promotes muscle inflammation via RPL35A-mediated translational reprogramming

Area of Science:

• Molecular Biology
• Immunology
• Toxicology

Background:

• Naja atra venom causes severe myotoxicity and inflammation, primarily mediated by snake venom phospholipase A2 (SVPLA2).
• The therapeutic potential of SVPLA2 inhibitors like varespladib is recognized, but the precise molecular mechanisms driving venom-induced pathology are not fully understood.

Purpose of the Study:

• To elucidate the dual molecular mechanisms by which SVPLA2 induces inflammation and myotoxicity.
• To investigate the roles of RPL35A and prostaglandin E2-activated p38 MAPK in venom-induced pathology.
• To evaluate the therapeutic potential of targeting these pathways.

Main Methods:

• Investigated translational regulation of IL-6 and TNF-α using RPL35A and PTBP1 interaction.
• Examined transcriptional regulation involving prostaglandin E2, p38 MAPK, NF-κB, and reactive oxygen species.
• Utilized AAV9-mediated RPL35A knockdown in mouse models for in vivo studies.
• Conducted in vitro experiments to assess therapeutic interventions.

Main Results:

• Identified a translational module where RPL35A-PTBP1 interaction enhances IL-6 and TNF-α translation without affecting mRNA levels.
• Uncovered a transcriptional axis involving prostaglandin E2, p38 MAPK, NF-κB, and reactive oxygen species, creating an inflammatory-oxidative cycle.
• Demonstrated that RPL35A knockdown and p38 inhibition synergistically reduce inflammation and tissue injury in vivo and in vitro.

Conclusions:

• SVPLA2 triggers pathology through coordinated transcriptional and translational mechanisms.
• The findings support the therapeutic potential of varespladib and highlight RPL35A as a non-canonical pro-inflammatory factor.
• Targeting RPL35A and the p38 MAPK pathway presents novel therapeutic avenues for treating venom-induced inflammation and potentially other inflammatory conditions.