Interferon lambda activates the immunoproteasome thereby potentially regulating anti-viral immunity in the lung

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Interferons (IFN) are the first line of defense against pathogens such as viruses. Both, type I and II interferons induce the immunoproteasome in virally infected cells. The immunoproteasome degrades intracellular proteins - including viral ones - into small peptides for presentation on MHC class I molecules on the cell surface to activate cytotoxic CD8+ T cell responses. However, little is known with regard to this regulation by type III interferons, such as IFNλ3, which mediate epithelium-specific immune responses. We here aimed to explore the regulation of immunoproteasome induction and activity by IFNλ3. Upon stimulation with IFNλ3, the three catalytic immunoproteasome subunits PSMB8 (LMP7), PSMB9 (LMP2) and PSMB10 (MECL1) were strongly upregulated in a concentration- and time dependent manner in the human lung epithelial cell line A549, both on the RNA and protein level as determined by RTqPCR and Western blotting. This coincided with induction of STAT1, a key signaling molecule of IFN signaling pathway. Importantly, elevated expression of the immunoproteasomal subunits resulted in de novo assembly of active immunoproteasomes as determined by activity-based probes specific for all catalytic active sites of the proteasome. These findings suggest that through induction of the immunoproteasome type III IFNs may play part in the activation of anti-viral immune responses of the epithelium, which we are currently investigating.

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