PMID- 33535228
OWN - NLM
STAT- MEDLINE
DCOM- 20210909
LR  - 20240226
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Print)
IS  - 0021-9525 (Linking)
VI  - 220
IP  - 3
DP  - 2021 Mar 1
TI  - Brd4 regulates NLRC4 inflammasome activation by facilitating IRF8-mediated 
      transcription of Naips.
LID - 10.1083/jcb.202005148 [doi]
LID - e202005148
AB  - NLRC4 inflammasome activation and the subsequent maturation of IL-1beta and IL-18 
      are critical for protection against infection by bacterial pathogens. The 
      epigenetic regulator Brd4 has emerged as a key player in inflammation by 
      regulating the expression of inflammatory cytokines. However, whether Brd4 has 
      any role in inflammasome activation remains undetermined. Here, we demonstrated 
      that Brd4 is an important regulator of NLRC4 inflammasome activation in response 
      to Salmonella typhimurium infection. Brd4-deficient bone marrow-derived 
      macrophages (BMDMs) displayed impaired caspase-1 activation, ASC oligomerization, 
      IL-1beta maturation, gasdermin-D cleavage, and pyroptosis in response to 
      S.typhimurium infection. RNA sequencing and RT-PCR results revealed that the 
      transcription of Naips was decreased in Brd4-deficient BMDMs. Brd4 formed a 
      complex with IRF8/PU.1 and bound to the IRF8 and PU.1 binding motifs on the 
      promoters of Naips to maintain the expression of Naips. Furthermore, myeloid 
      lineage-specific Brd4 conditional knockout mice were more susceptible to 
      S.typhimurium infection with increased mortality, bacterial loads, and tissue 
      damage; impaired inflammasome-dependent cytokine production; and pyroptosis. Our 
      studies identify a novel function of Brd4 in innate immunity by controlling 
      inflammasome-mediated cytokine release and pyroptosis to effectively battle 
      S.typhimurium infection.
CI  - (c) 2021 Dong et al.
FAU - Dong, Xingchen
AU  - Dong X
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL.
FAU - Hu, Xiangming
AU  - Hu X
AD  - Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative 
      Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, 
      Fujian Medical University, Fuzhou, China.
FAU - Bao, Yan
AU  - Bao Y
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL.
FAU - Li, Guo
AU  - Li G
AD  - Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative 
      Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, 
      Fujian Medical University, Fuzhou, China.
FAU - Yang, Xiao-Dong
AU  - Yang XD
AD  - Shanghai Institute of Immunology, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Slauch, James M
AU  - Slauch JM
AD  - Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, 
      IL.
AD  - Carl R. Woese Institute for Genomic Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL.
FAU - Chen, Lin-Feng
AU  - Chen LF
AD  - Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, 
      IL.
AD  - Carl R. Woese Institute for Genomic Biology, University of Illinois at 
      Urbana-Champaign, Urbana, IL.
LA  - eng
GR  - R01 AI123381/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Brd4 protein, mouse)
RN  - 0 (CARD Signaling Adaptor Proteins)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Gsdmd protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interferon Regulatory Factors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Ipaf protein, mouse)
RN  - 0 (Neuronal Apoptosis-Inhibitory Protein)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphate-Binding Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pycard protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 0 (interferon regulatory factor-8)
RN  - 0 (proto-oncogene protein Spi-1)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins/*metabolism
MH  - Base Sequence
MH  - CARD Signaling Adaptor Proteins/metabolism
MH  - Calcium-Binding Proteins/*metabolism
MH  - CpG Islands/genetics
MH  - Inflammasomes/*metabolism
MH  - Interferon Regulatory Factors/*metabolism
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Macrophages/metabolism
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Neuronal Apoptosis-Inhibitory Protein/genetics/metabolism
MH  - Nuclear Proteins/deficiency/*metabolism
MH  - Phosphate-Binding Proteins/metabolism
MH  - Protein Binding
MH  - Proto-Oncogene Proteins/metabolism
MH  - Pyroptosis
MH  - Salmonella typhimurium/physiology
MH  - Trans-Activators/metabolism
MH  - Transcription Factors/deficiency/*metabolism
MH  - *Transcription, Genetic
MH  - Mice
PMC - PMC7863722
EDAT- 2021/02/04 06:00
MHDA- 2021/09/10 06:00
PMCR- 2021/09/01
CRDT- 2021/02/03 20:08
PHST- 2020/05/28 00:00 [received]
PHST- 2020/11/13 00:00 [revised]
PHST- 2020/12/22 00:00 [accepted]
PHST- 2021/02/03 20:08 [entrez]
PHST- 2021/02/04 06:00 [pubmed]
PHST- 2021/09/10 06:00 [medline]
PHST- 2021/09/01 00:00 [pmc-release]
AID - 211747 [pii]
AID - jcb.202005148 [pii]
AID - 10.1083/jcb.202005148 [doi]
PST - ppublish
SO  - J Cell Biol. 2021 Mar 1;220(3):e202005148. doi: 10.1083/jcb.202005148.