E3 ubiquitin ligase SYVN1 mediates K63-linked ubiquitination of DDX3X to activate Macrophage NLRP3 Inflammasome

A recent study has uncovered the crucial role of the E3 ubiquitin ligase SYVN1 (Synoviolin) in the regulation of DDX3X (DEAD box helicase 3, X linked) and its impact on the NLRP3 inflammasome and stress granules. DDX3X is a vital component of both stress granules and the NLRP3 inflammasome assembly, but the upstream cellular stress signals that drive DDX3X to activate these contrasting cellular pathways have remained unclear until now.

The researchers found that SYVN1 silencing in macrophages led to a decrease in both NLRP3-driven inflammation and stress granule formation. Furthermore, SYVN1 deficiency was observed to prevent LPS-induced inflammatory lung injury and increase the survival rate of mice. This is because SYVN1 sustains DDX3X gene expression and promotes stimulus-dependent ubiquitination of DDX3X.

Under inflammatory conditions, SYVN1 mediated 63-linked ubiquitination of DDX3X, which is crucial for NLRP3 inflammasome activation. However, under stress conditions, the K63-linked DDX3X ubiquitination was reduced in coordination with the activity of the deubiquitinase OTUB1 (OTU domain-containing ubiquitin aldehyde-binding protein 1).

The study reveals that the delicate balance between SYVN1 and OTUB1 functions to optimize DDX3X activity and the activation of NLRP3 or stress granules. This discovery points towards ubiquitination of DDX3X as a potential therapeutic target for inflammasome-driven inflammation.