Regulation of Immune Gene expression and inflammatory diseases by the Cellular nucleic acid binding protein (CNBP)
Yongzhi Chen | Fitzgerald Lab | Charles A. King Trust Postdoctoral Research Fellowship
An inducible program of inflammatory gene expression is a hallmark of antimicrobial defenses. Germline-encoded receptors recognize microbial products and activate signaling pathways that lead to the expression of hundreds of inflammatory response genes. This proposal expands on these studies by defining a new regulator of immune gene expression; the CCHC-type zinc finger protein cytosolic nucleic acid binding protein (CNBP). We have generated mice lacking CNBP and found that CNBP-deficient macrophages fail to induce transcription of the IL-12/IL23 family. Cnbp resides in the cytosol of macrophages and translocates to the nucleus in response to multiple microbial ligands and pathogens. Cnbp regulates IL12 via c-Rel, an NFkB/Rel family member known to control IL12b gene transcription. c-Rel nuclear translocation and DNA binding activity require Cnbp. Furthermore, Cnbp itself a DNA binding protein bound the IL12b promoter. CNBP-deficient mice were more susceptible to acute toxoplasmosis associated with reduced production of IL12b, as well as a reduced Th1 cell IFNg response essential to control parasite replication. Collectively, these findings identify Cnbp as a new signaling molecule downstream of multiple Pattern Recognition Receptors, that acts as a key regulator of IL12b gene transcription and Th1 immunity. This proposal will test the hypothesis that CNBP represents a novel signaling molecule that acts as a transcriptional coactivator to bind the genome and coordinate expression of IL12p40 to regulate IL12 and IL23 in innate cells and direct TH1/TH17 dependent adaptive immunity and inflammation. We will explore these hypotheses using the following specific aims: (1) defining detailed molecular mechanisms of CNBP-dependent control of the IL12/IL23 gene family; (2) defining the cell type specific contributions of CNBP in control of Th1 immunity to Toxoplasma gondii and TH17 responses to Candida Albicans; and (3) defining the role of CNBP in controlling Inflammatory Bowel Diseases using DSS colitis and related models.
