title: Zinc finger protein ZBTB20 promotes Toll-like receptor-triggered innate immune responses by repressing IκBα gene transcription.
abstract: Toll-like receptor (TLR) signaling is critical in innate response against invading pathogens. However, the molecular mechanisms for full activation of TLR-triggered innate immunity need to be fully elucidated. The broad complex tramtrack bric-a-brac/poxvirus and zinc finger (BTB/POZ) family is a class of transcription factors involved in many biological processes. However, few BTB/POZ proteins were reported to function in innate immune response. Zinc finger and BTB domain-containing 20 (ZBTB20), a member of BTB/POZ family, functions in neurogenesis and represses α-fetoprotein gene transcription in liver. However, the immunological functions of ZBTB20 remain unknown. Here, we found that myeloid cell-specific ZBTB20 KO mice were resistant to endotoxin shock and Escherichia coli-caused sepsis. ZBTB20 deficiency attenuated TLR-triggered production of proinflammatory cytokines and type I IFN in macrophages, which attributed to higher abundance of IκBα protein and impaired activity of NF-κB. Furthermore, ChIP and next generation high-throughput DNA sequencing assay showed that ZBTB20 specifically bound to IκBα gene promoter (+1 to +60 region) after TLR activation. ZBTB20 could inhibit IκBα gene transcription, govern IκBα protein expression, and then promote NF-κB activation. Therefore, transcriptional repressor ZBTB20 is needed to promote full activation of TLR signaling and TLR-triggered innate immune response by selectively suppressing the suppressor IκBα gene transcription.
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Bao
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Han
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhan
authors.forename: Jun
authors.initials: J
authors.lastname: Meng
authors.forename: Yingke
authors.initials: Y
authors.lastname: Li
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Weiping J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology; D013489:Suppression, Genetic; D051193:Toll-Like Receptors / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D051193:Toll-Like Receptors; D014157:Transcription Factors; C520426:Zbtb20 protein, mouse; D000072000:NF-KappaB Inhibitor alpha