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Title: RUVBL1/2 complex regulates pro-inflammatory responses in macrophages via regulating histone H3K4 trimethylation
Authors: Zhang, R 
Cheung, CY 
Seo, SU
Liu, H 
Pardeshi, L
Wong, KH
Chow, LMC 
Chau, MP 
Wang, Y 
Lee, AR
Kwon, WY
Chen, S
Chan, BKW 
Wong, K
Choy, RKW
Ko, BCB 
Issue Date: Jun-2021
Source: Frontiers in immunology, June 2021, v. 12, 679184
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.
Keywords: Epigenetic modulation
H3K4 trimethylation
Macrophages
Pro-inflammatory
RUVBL1/2
Publisher: Frontiers Research Foundation
Journal: Frontiers in immunology 
EISSN: 1664-3224
DOI: 10.3389/fimmu.2021.679184
Rights: © 2021 Zhang, Cheung, Seo, Liu, Pardeshi, Wong, Chow, Chau, Wang, Lee, Kwon, Chen, Chan, Wong, Choy and Ko. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The following publication Zhang R, Cheung CY, Seo S-U, Liu H, Pardeshi L, Wong KH, Chow LMC, Chau MP, Wang Y, Lee AR, Kwon WY, Chen S, Chan BK-w, Wong K, Choy RKW and Ko BCB (2021) RUVBL1/2 Complex Regulates Pro-Inflammatory Responses in Macrophages via Regulating Histone H3K4 Trimethylation. Front. Immunol. 12:679184 is available at https://doi.org/10.3389/fimmu.2021.679184
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