Immunoproteasomes shape the transcriptome and regulate the function of dendritic cells (IRM7P.476)

Abstract Background: By regulating protein degradation, constitutive proteasomes (CPs) regulate practically all fundamental cellular processes. Vertebrates also express immunoproteasomes (IPs), but the only well-established non-redundant role for IPs is their enhanced ability to generate peptides for MHC-I presentation. Results: Here we show that IPs regulate the expression of 8,104 genes in maturing bone marrow-derived dendritic cells (DCs). IPs regulated transcription of many mRNAs and maturation of a subset of them. These genes were separated into 15 different kinetic patterns, and Gene-Ontology analysis revealed enrichment linked to immune functions and housekeeping cellular processes, highlighting the complexity of the transcriptional cascade regulated by IPs. Notably, IPs’ impact on transcription was mediated through the non-redundant regulation of critical immune-related pathways, such as Nf-kB, STATs and IRFs. Furthermore, even when loaded with optimal amounts of SIINFEKL, IP-deficient DCs were inefficient for in vivo priming of OT-1 T cells. Conclusion: Our study shows that the role of IPs is not limited to antigen processing and highlights a new and critical role for IPs in regulation of gene expression. The dramatic impact of IPs on the transcriptional landscape could explain the various immune and non-immune phenotypes observed in vertebrates with IP-deficiency or -mutation.