RRC ID 76197
Author Irfan Afridi M, Zheng Z, Liu J, Liu L, Zhang S, Zhu Z, Peng Y, Zhou D, Tu H.
Title The bZIP transcription factor BATF3/ZIP-10 suppresses innate immunity by attenuating PMK-1/p38 signaling.
Journal Int Immunol
Abstract Innate immunity is the first line of host defense against pathogenic invasion in metazoans. The transcription factor basic leucine zipper transcriptional factor ATF-like 3 (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 immune responses remains unclear. Here, we show an evolutionarily conserved basic-region leucine zipper (bZIP) transcription factor BATF3/ZIP-10 suppresses innate immune response through repressing the p38/PMK-1 mitogen-activated protein kinase (MAPK) pathway in vitro and in vivo. The worm mutant lacking the Caenorhabditis 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 the 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 RNA-interference knockdown exhibited a reduction or increase of the cell viability upon Pseudomonas aeruginosa PA14 infection, respectively. The overexpression of either worm ZIP-10 or human BATF3 abolished the activation of p38 and inhibited the expression of antimicrobial peptides 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 innate immunity by attenuating the p38 MAPK signaling activity, which expands our understanding of the pathological mechanisms underlying relevant infectious diseases.
Volume 35(4)
Pages 181-196
Published 2023-4-4
DOI 10.1093/intimm/dxac053
PII 6835612
PMID 36409527
MeSH Animals Basic-Leucine Zipper Transcription Factors / genetics Basic-Leucine Zipper Transcription Factors / metabolism Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins* / genetics Caenorhabditis elegans Proteins* / metabolism HEK293 Cells Humans Immunity, Innate Mice MicroRNAs* / genetics Mitogen-Activated Protein Kinases / genetics Mitogen-Activated Protein Kinases / metabolism Pseudomonas Infections* Transcription Factors / metabolism p38 Mitogen-Activated Protein Kinases / metabolism
C.elegans tm2813 tm1924