We have shown that IRF8 is required for bone marrow progenitor cells to differentiate into macrophages and subsets of DCs that produce type I IFNs as well as the IL-12 cytokine. We have shown that IRF8 is critical not only for DC development but is essential for their function, namely IFN transcription in DCs. IRF8 amplifies IFN transcription in the feedback phase following the initial transcription activated by IRF7. Chromatin immunoprecipitation analysis showed that IRF8 binds to the promoter region of IFN genes and facilitates sustained RNA polymerase II recruitment to the promoters. In a separate study we found that IRF8 and many other nuclear proteins are ubiquitinated in macrophages after IFN and toll like receptor signaling. By immunopurification and massspectrometry, we identified a novel ubiquitin ligase Ro52 that interacts with and ubiquitinates IRF8. Ro52 is a tripartite motif family protein and carries the RING domain, a ubiquitin ligase motif and the SPRY domain. Ro52 has been known as an autoantigen present in patients with systemic lupus erythematosus (SLE) and Sogrens disease and its expression is induced by IFNs. Functional analysis indicates that Ro52 mediated ubiquitination results in enhanced transcription of IL12p40, rather than stimulating IRF8 degradation. The role of Ro52 is being studied using Ro52 knock-out mice constructed in collaboration with Dr. Morse in NIAID.
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