Deacetylation via SIRT2 prevents keratin-mutation-associated injury and keratin aggregation

被引:3
|
作者
Sun, Jingyuan [1 ,2 ]
Li, Pei [1 ]
Gui, Honglian [3 ]
Rittie, Laure [4 ,11 ]
Lombard, David B. [5 ,6 ]
Rietscher, Katrin [7 ]
Magin, Thomas M. [7 ]
Xie, Qing [3 ]
Liu, Li [8 ,9 ]
Omary, M. Bishr [1 ,10 ]
机构
[1] Rutgers State Univ, Ctr Adv Biotechnol & Med, 679 Hoes Lane West,Room 206, Piscataway, NJ 08854 USA
[2] Southern Med Univ, Nanfang Hosp, Dept Radiat Oncol, Guangzhou, Peoples R China
[3] Jiaotong Univ, Ruijin Hosp, Sch Med, Dept Infect Dis, 197 Ruijin Er Rd, Shanghai 200025, Peoples R China
[4] Univ Michigan, Dept Dermatol, Ann Arbor, MI USA
[5] Univ Miami, Sylvester Comprehens Canc Ctr, Miller Sch Med, Miami, FL USA
[6] Univ Miami, Dept Pathol & Lab Med, Miller Sch Med, Miami, FL USA
[7] Univ Leipzig, Inst Biol, Div Cell & Dev Biol, Leipzig, Germany
[8] Southern Med Univ, Nanfang Hosp, Hepatol Unit, 1838 North Guangzhou Ave, Guangzhou 510515, Peoples R China
[9] Southern Med Univ, Nanfang Hosp, Dept Infect Dis, 1838 North Guangzhou Ave, Guangzhou 510515, Peoples R China
[10] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI USA
[11] GlaxoSmithKline Pharmaceut Res & Dev, Collegeville, PA USA
基金
中国国家自然科学基金;
关键词
EPIDERMOLYSIS-BULLOSA SIMPLEX; NICOTINAMIDE MONONUCLEOTIDE PROTECTS; INTERMEDIATE-FILAMENT PROTEINS; SIMPLE EPITHELIAL KERATINS; NF-KAPPA-B; TRANSGENIC MICE; POSTTRANSLATIONAL MODIFICATIONS; PARTHENOLIDE; PHOSPHORYLATION; CELLS;
D O I
10.1172/jci.insight.166314
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Keratin (K) and other intermediate filament (IF) protein mutations at conserved arginines disrupt keratin filaments into aggregates and cause human epidermolysis bullosa simplex (EBS; K14-R125C) or predispose to mouse liver injury (K18-R90C). The challenge for more than 70 IF-associated diseases is the lack of clinically utilized IF-targeted therapies. We used high throughput drug screening to identify compounds that normalized mutation-triggered keratin filament disruption. Parthenolide, a plant sesquiterpene lactone, dramatically reversed keratin filament disruption and protected cells and mice expressing K18-R90C from apoptosis. K18-R90C became hyperacetylated compared with K18-WT and treatment with parthenolide normalized K18 acetylation. Parthenolide upregulated the NAD-dependent SIRT2, and increased SIRT2-keratin association. SIRT2 knockdown or pharmacologic inhibition blocked the parthenolide effect, while site-specific Lys-to-Arg mutation of keratin acetylation sites normalized K18-R90C filaments. Treatment of K18-R90C-expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect. In 2 human K18 variants that associate with human fatal drug-induced liver injury, parthenolide protected K18-D89H- but not K8-K393R-induced filament disruption and cell death. Importantly, parthenolide normalized K14-R125C-mediated filament disruption in keratinocytes and inhibited dispase-triggered keratinocyte sheet fragmentation and Fas-mediated apoptosis. Therefore, keratin acetylation may provide a novel therapeutic target for some keratin-associated diseases.
引用
收藏
页数:16
相关论文
共 29 条
  • [1] Mammalian SIRT2 suppresses skin tumorigenesis and keratin 19 expression
    Ming, M.
    Qiang, L.
    Zhao, B.
    He, Y.
    JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2014, 134 : S34 - S34
  • [2] Glucose and SIRT2 reciprocally mediate the regulation of keratin 8 by lysine acetylation
    Snider, Natasha T.
    Leonard, Jessica M.
    Kwan, Raymond
    Griggs, Nicholas W.
    Rui, Liangyou
    Omary, M. Bishr
    JOURNAL OF CELL BIOLOGY, 2013, 200 (03): : 241 - 247
  • [3] Mammalian SIRT2 inhibits keratin 19 expression and is a tumor suppressor in skin
    Ming, Mei
    Qiang, Lei
    Zhao, Baozhong
    He, Yu-Ying
    EXPERIMENTAL DERMATOLOGY, 2014, 23 (03) : 207 - 209
  • [4] SIRT2 Prevents Cisplatin-Induced Neuron Injury By Promoting Nucleotide Excision Repair
    Zhang, M.
    Du, W.
    Acklin, S.
    Jin, S.
    Xia, F.
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2019, 105 (01): : S220 - S220
  • [5] SIRT2 prevents cisplatin-induced peripheral neuron injury by enhancing nucleotide excision repair
    Acklin, S.
    Zhang, M.
    Du, W.
    Jin, S.
    Xia, F.
    RADIOTHERAPY AND ONCOLOGY, 2020, 152 : S26 - S26
  • [6] PP2 protects from keratin mutation-associated liver injury and filament disruption via SRC kinase inhibition in male but not female mice
    Li, Pei
    Maitra, Dhiman
    Kuo, Ning
    Kwan, Raymond
    Song, Yang
    Tang, Weiliang
    Chen, Lu
    Xie, Qing
    Liu, Li
    Omary, M. Bishr
    HEPATOLOGY, 2023, 77 (01) : 144 - 158
  • [7] SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B
    Ye, Yanxia
    Yang, Kuan
    Liu, Haisong
    Yu, Yang
    Song, Moshi
    Huang, Daoyuan
    Lei, Jinghui
    Zhang, Yiyuan
    Liu, Zunpeng
    Chu, Qun
    Fan, Yanling
    Zhang, Sheng
    Jing, Yaobin
    Esteban, Concepcion Rodriguez
    Wang, Si
    Belmonte, Juan Carlos Izpisua
    Qu, Jing
    Zhang, Weiqi
    Liu, Guang-Hui
    NATURE AGING, 2023, 3 (10): : 1269 - +
  • [8] SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B
    Yanxia Ye
    Kuan Yang
    Haisong Liu
    Yang Yu
    Moshi Song
    Daoyuan Huang
    Jinghui Lei
    Yiyuan Zhang
    Zunpeng Liu
    Qun Chu
    Yanling Fan
    Sheng Zhang
    Yaobin Jing
    Concepcion Rodriguez Esteban
    Si Wang
    Juan Carlos Izpisua Belmonte
    Jing Qu
    Weiqi Zhang
    Guang-Hui Liu
    Nature Aging, 2023, 3 : 1269 - 1287
  • [9] SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury
    Zhang, Yingting
    Long, Xidai
    Ruan, Xin
    Wei, Qian
    Zhang, Lin
    Wo, Lulu
    Huang, Dongdong
    Lin, Longshuai
    Wang, Difei
    Xia, Li
    Zhao, Qinghua
    Liu, Junling
    Zhao, Qian
    He, Ming
    CELL DISCOVERY, 2021, 7 (01)
  • [10] SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury
    Yingting Zhang
    Xidai Long
    Xin Ruan
    Qian Wei
    Lin Zhang
    Lulu Wo
    Dongdong Huang
    Longshuai Lin
    Difei Wang
    Li Xia
    Qinghua Zhao
    Junling Liu
    Qian Zhao
    Ming He
    Cell Discovery, 7