RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation

Rui Zhang, Chris Y. Cheung, Sang Uk Seo, Hang Liu, Lakhansing Pardeshi, Koon Ho Wong, Larry M.C. Chow, Mary P. Chau, Yixiang Wang, Ah Ra Lee, Woon Yong Kwon, Sheng Chen, Bill Kwan wai Chan, Kenneth Wong, Richard K.W. Choy, Ben C.B. Ko

Research output: Journal article publicationJournal articleAcademic researchpeer-review

Abstract

Macrophages play an important role in the host defense mechanism. In response to infection, macrophages activate a genetic program of pro-inflammatory response to kill any invading pathogen, and initiate an adaptive immune response. We have identified RUVBL2 - an ATP-binding protein belonging to the AAA+ (ATPase associated with diverse cellular activities) superfamily of ATPases - as a novel regulator in pro-inflammatory response of macrophages. Gene knockdown of Ruvbl2, or pharmacological inhibition of RUVBL1/2 activity, compromises type-2 nitric oxide synthase (Nos2) gene expression, nitric oxide production and anti-bacterial activity of mouse macrophages in response to lipopolysaccharides (LPS). RUVBL1/2 inhibitor similarly inhibits pro-inflammatory response in human monocytes, suggesting functional conservation of RUVBL1/2 in humans. Transcriptome analysis further revealed that major LPS-induced pro-inflammatory pathways in macrophages are regulated in a RUVBL1/2-dependent manner. Furthermore, RUVBL1/2 inhibition significantly reduced the level of histone H3K4me3 at the promoter region of Nos2 and Il6, two prototypical pro-inflammatory genes, and diminished the recruitment of NF-kappaB to the corresponding enhancers. Our study reveals RUVBL1/2 as an integral component of macrophage pro-inflammatory responses through epigenetic regulations, and the therapeutic potentials of RUVBL1/2 inhibitors in the treatment of diseases caused by aberrant activation of pro-inflammatory pathways.

Original languageEnglish
Article number679184
JournalFrontiers in Immunology
Volume12
DOIs
Publication statusPublished - 4 Jun 2021

Keywords

  • epigenetic modulation
  • H3K4 trimethylation
  • macrophages
  • pro-inflammatory
  • RUVBL1/2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this