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 cellspecific ZBTB20 KO mice were resistant to endotoxin shock and Escherichia coli-caused sepsis. ZBTB20 deficiency attenuated TLRtriggered 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.

Zbtb20 regulates the terminal differentiation of hypertrophic chondrocytes via repression of Sox9

“…Interestingly, loss of Zbtb20 resulted in the ectopic expression of Sox9 in the late hypertrophic zone, suggesting that Zbtb20 positively regulates terminal maturation, at least partially, by inhibiting Sox9 expression. Although this fits the notion that Zbtb20 functions primarily as a transcriptional repressor (Liu et al, 2013;Xie et al, 2008;Zhang et al, 2012), ChIP and luciferase reporter assays did not support direct binding of Zbtb20 to the Sox9 promoter to regulate transcriptional activity. One possibility is that Zbtb20 regulates Sox9 transcription via a cis-acting element that is located outside of the sequence that we analyzed, such as a distal enhancer.…”

“…Zbtb20 null mice exhibit severe postnatal growth retardation, metabolic dysfunction and lethality, suggesting that Zbtb20 plays nonredundant roles in multiple organ systems (Sutherland et al, 2009). Furthermore, conditional gene targeting demonstrates that Zbtb20 regulates insulin secretion in pancreatic β cells (Zhang et al, 2012), promotes Toll-like receptor-mediated innate immune response in macrophages (Liu et al, 2013), and modulates pain sensation in nociceptive sensory neurons (Ren et al, 2014).…”

Death Domain-associated Protein 6 (Daxx) Selectively Represses IL-6 Transcription through Histone Deacetylase 1 (HDAC1)-mediated Histone Deacetylation in Macrophages

“…Cell Culture and Transfection-Murine macrophage cell line RAW264.7 and human HEK293T cell line were obtained from American Type Culture Collection and cultured as described previously (26). The cells were transfected with JetPEI (PolyPlus) for plasmid DNA.…”

“…The cells were transfected with JetPEI (PolyPlus) for plasmid DNA. Thioglycolate-elicited mouse primary peritoneal macrophages were prepared and cultured as described previously (26).…”

Human Dental Pulp Stem Cells via the NF-κB Pathway

“…It belongs to a class of nuclear DNA-binding transcription factors which are implicated in many developmental processes [8]. ZBTB20 knockout mice display abnormal glucose homeostasis, impaired hormonal responses, and depletion of energy stores, consistent with an energetic deficit [9].…”