PRRSV-2 nsp2 Ignites NLRP3 inflammasome through IKKβ-dependent dispersed trans-Golgi network translocation.

Summary

This mechanistic study shows that PRRSV-2 nsp2 directly engages the NLRP3 NACHT domain, recruits IKKβ, and drives NLRP3 translocation to the dispersed trans-Golgi network, enabling ASC polymerization and inflammasome activation. The IKKβ-dependent dTGN translocation was also required for PRV- and EMCV-induced inflammatory responses, indicating a broader, virus-agnostic pathway.

Key Findings

• PRRSV-2 nsp2 binds the NLRP3 NACHT domain and recruits IKKβ.
• IKKβ-dependent translocation of NLRP3 to the dTGN promotes oligomerization and ASC polymerization.
• The same IKKβ–dTGN mechanism is pivotal for PRV- and EMCV-induced inflammatory responses.

Clinical Implications

Targeting the IKKβ–NLRP3 axis or the trafficking of NLRP3 to the dTGN could attenuate hyperinflammatory lung injury in severe viral pneumonias, though human validation is needed.

Limitations

• Primarily nonhuman viral systems; limited direct human ARDS data
• Translational relevance needs validation in human lung cells and in vivo models

Future Directions

Test pharmacologic IKKβ/NLRP3 modulators, assess dTGN trafficking inhibitors, and validate signatures in human ARDS samples and relevant in vivo models.