Histone Deacetylase 3 Couples Mitochondria to Drive IL-1β-Dependent Inflammation by Configuring Fatty Acid Oxidation

被引：127

作者：

Chi, Zhexu ^{[1
,2
]}

Chen, Sheng ^{[1
,2
,6
]}

Xu, Ting ^{[1
,2
]}

Zhen, Wenxuan ^{[3
]}

Yu, Weiwei ^{[1
,2
]}

Jiang, Danlu ^{[1
,2
]}

Guo, Xingchen ^{[8
]}

Wang, Zhen ^{[1
,2
]}

Zhang, Kailian ^{[1
,2
]}

Li, Mobai ^{[1
,2
]}

Zhang, Jian ^{[1
,2
]}

Fang, Hui ^{[1
,2
]}

Yang, Dehang ^{[1
,2
]}

Ye, Qizhen ^{[1
,2
]}

Yang, Xuyan ^{[4
]}

Lin, Hui ^{[5
]}

Yang, Fan ^{[3
]}

Zhang, Xue ^{[7
]}

Wang, Di ^{[1
,2
]}

机构：

[1] Zhejiang Univ, Sch Med, Inst Immunol, Sir Run Run Shaw Hosp, Hangzhou 310058, Peoples R China

[2] Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Orthopaed Surg, Hangzhou 310058, Peoples R China

[3] Zhejiang Univ, Sch Med, Dept Biophys, Hangzhou 310058, Peoples R China

[4] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Rheumatol, Hangzhou 310058, Peoples R China

[5] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Gen Surg, Hangzhou 310058, Peoples R China

[6] Zhejiang Univ, Sch Med, Dept Colorectal Surg & Oncol, Minist Educ,Affiliated Hosp 2,Key Lab Canc Preven, Hangzhou 310058, Peoples R China

[7] Zhejiang Univ, Sch Med, Dept Pathol & Pathophysiol, Hangzhou 310058, Peoples R China

[8] Wuhan Univ, Coll Life Sci, State Key Lab Virol, Wuhan 430072, Peoples R China

来源：

MOLECULAR CELL | 2020年 / 80卷 / 01期

基金：

中国国家自然科学基金;

关键词：

NLRP3; INFLAMMASOME; METABOLISM; INHIBITOR; CANCER; CELLS; HDAC3; IMMUNOMETABOLISM; IL-1-BETA;

D O I：

10.1016/j.molcel.2020.08.015

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1 beta production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit alpha. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1 beta-dependent inflammation.

引用

页码：43 / +

页数：23

共 55 条

[21]

ETOMOXIR, A CARNITINE PALMITOYLTRANSFERASE-I INHIBITOR, PROTECTS HEARTS FROM FATTY ACID-INDUCED ISCHEMIC-INJURY INDEPENDENT OF CHANGES IN LONG-CHAIN ACYLCARNITINE [J].