The bZIP Transcription Factor BATF3/ZIP-10 Suppresses Innate Immunity by Attenuating PMK-1/p38 Signaling.

Innate immunity is the first line of host defense against pathogenic invasion in metazoans. The transcription factor BATF3 plays a crucial role in the development of conventional dendritic cells and the program of CD8 + T cell survival and memory, but the role of BATF3 in innate immunity response remains unclear. Here, we show an evolutionarily conserved basic-region leucine zipper (bZIP) transcription factor BATF3/ZIP-10 suppresses innate immune response through repressing p38/PMK-1 MAPK pathway in vitro and in vivo. The worm mutant lacking C. elegans homolog BATF3, ZIP-10, exhibited enhanced resistance to PA14 infection, which was completely rescued by transgenic expression of either endogenous zip-10 or mouse or human Batf3 cDNA driven by worm zip-10 promoter. ZIP-10 expression was inhibited by a microRNA miR-60 that was downregulated upon PA14 infection. Moreover, the level of phosphorylated but not total PMK-1/p38 was attenuated by ZIP-10 and stimulated by miR-60. The human HEK293 cells with Batf3 overexpression or RNAi knockdown exhibited the reduction or increase of the cell viability upon P. aeruginosa PA14 infection, respectively. The overexpression of either worm ZIP-10 or human BATF3 abolished the activation of p38 and inhibited the expression of the antimicrobial peptide and cytokine genes in HEK293 cells. Our findings indicate that the genetic transcriptional program of the evolutionally conserved bZIP transcription factor BATF3/ZIP-10 suppresses the innate immunity by attenuating the p38 MAPK signaling activity, which expands our understanding of the pathological mechanisms underlying relevant infectious diseases.