The Role of the Phylogenetically Conserved Cochaperone Protein Droj2/DNAJA3 in NF-κB Signaling

The NF-κB pathway is a phylogenetically conserved signaling pathway with a central role in inflammatory and immune responses. Here we demonstrate that a cochaperone protein, Droj2/DNAJA3, is involved in the activation of canonical NF-κB signaling in flies and in human cultured cells. Overexpression of Droj2 induced the expression of an antimicrobial peptide in Drosophila. Conversely, Droj2 knockdown resulted in reduced expression of antimicrobial peptides and higher susceptibility to Gram-negative bacterial infection in flies. Similarly, Toll-like receptor-stimulated IκB phosphorylation and NF-κB activation were suppressed by DNAJA3 knockdown in HEK293 cells. IκB kinase overexpression-induced NF-κB phosphorylation was also compromised in DNAJA3 knockdown cells. Our study reveals a novel conserved regulator of the NF-κB pathway acting at the level of IκB phosphorylation. Background: The NF-κB pathway is crucial for the regulation of immune responses, inflammation, and stress responses. Results: The cochaperone protein Droj2/DNAJA3 is required to activate NF-κB signaling in flies and human cultured cells. Conclusion: Droj2/DNAJA3 is a newly identified evolutionarily conserved regulator of NF-κB signaling. Significance: A novel evolutionarily conserved regulator of NF-κB signaling was identified by Drosophila genetic screening.