Protein-protein and DNA-protein interactions affect the activity of lymphoid-specific IFN regulatory factors

IFN regulatory factors (IRFs) constitute a family of transcription factors that are involved in IFN signaling and the development and differentiation of the immune system. Targeted gene disruption studies in mice assigned the ir primary role to the immune system. Two lymphoid-specific IRF members, IF N consensus sequence binding protein (ICSBP) and IRF-4, bind target DNA wit h greater efficiency following interaction with two transcription factors, PU,I and E47, leading to transcriptional synergy. PU,I and E47 are essentia l for proper differentiation and maturation of lymphoid cells, In addition, ICSBP interacts with two IRF members, IRF-1 and IRF-2, which also have cen tral roles in the regulation of cell-mediated immunity. Previously, we iden tified a region in ICSBP, termed the IRF association domain (IAD), that is conserved in all IRFs (excluding IRF-1 and IRP-2) and is essential for its interactions with other IRF proteins, Here we show that the IAD is an indep endent module used by ICSBP and IRF-4 For protein-protein interactions, In addition, an IAD of IRF-2 (LAD2), necessary for interaction with ICSBP, was identified and found to be conserved in IRF-1, The IAD2 shares similar cha racteristics with the PEST domain that Is essential for the interaction of PU.1 with IRF-4, We also show that the ICSBP DNA binding domain is indispen sable for the formation of DNA binding heterocomplexes and transcriptional activity. Therefore, our results shed light on the molecular mechanisms tha t affect TRF activities in the immune system via discrete functional domain s.