Sirtuin 6 (SIRT6) regulates redox homeostasis and signaling events in human articular chondrocytes.
Sirtuin 6 (SIRT6) regulates redox homeostasis and signaling events in human articular chondrocytes.
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DOI：
10.1016/j.freeradbiomed.2021.01.054
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发表时间：
2021-04
影响因子：
7.4
通讯作者：
Loeser RF
中科院分区：
文献类型：
--
作者：
Collins JA;Kapustina M;Bolduc JA;Pike JFW;Diekman BO;Mix K;Chubinskaya S;Eroglu E;Michel T;Poole LB;Furdui CM;Loeser RF
核定位的蛋白质脱乙酰基酶，SIRT6，已被确定为驱动衰老的生物过程的关键调节剂。在这些过程中，SIRT6可以促进对氧化应激条件的抵抗，但确切的机制仍不清楚。本研究的目的是检查SIRT6活性的调节年龄和氧化应激，并确定SIRT6在维持关节软骨细胞氧化还原稳态的作用。虽然SIRT6水平不随年龄变化，但在从老年人分离的软骨细胞中，SIRT6活性显著降低。使用基于双甲酮的化学探针检测氧化的半胱氨酸，我们确定SIRT6在氧化应激条件下被氧化，这是一种与SIRT6活性降低相关的效应。通过腺病毒SIRT6过表达增强SIRT6活性，特异性地增加了两种抗氧化蛋白的基础水平，过氧化物酶1（Prx 1）和硫氧还蛋白（Srx），并降低了抗氧化活性抑制剂硫氧还蛋白相互作用蛋白（TXNIP）的水平。相反，在来自软骨特异性Sirt6敲除小鼠的软骨细胞中，Sirt6缺失降低了Prx1水平，增加了TXNIP水平。SIRT6过表达降低了核产生的H2O2水平和氧化应激诱导的核磷酸化p65的积累。我们的数据表明，SIRT6活性随着年龄和与衰老相关的氧化应激条件而改变。SIRT6通过调节Prx催化循环的特定成员来促进软骨细胞氧化还原稳态。旨在预防SIRT6活性与年龄相关性下降的靶向治疗可能代表了一种新的策略，以维持关节组织中的氧化还原平衡并减少与骨关节炎（OA）有关的分解代谢信号事件。
The nuclear localized protein deacetylase, SIRT6, has been identified as a crucial regulator of biological processes that drive aging. Among these processes, SIRT6 can promote resistance to oxidative stress conditions, but the precise mechanisms remain unclear. The objectives of this study were to examine the regulation of SIRT6 activity by age and oxidative stress and define the role of SIRT6 in maintaining redox homeostasis in articular chondrocytes. Although SIRT6 levels did not change with age, SIRT6 activity was significantly reduced in chondrocytes isolated from older adults. Using dimedone-based chemical probes that detect oxidized cysteines, we identified that SIRT6 is oxidized in response to oxidative stress conditions, an effect that was associated with reduced SIRT6 activity. Enhancement of SIRT6 activity through adenoviral SIRT6 overexpression specifically increased the basal levels of two antioxidant proteins, peroxiredoxin 1 (Prx1) and sulfiredoxin (Srx) and decreased the levels of an inhibitor of antioxidant activity, thioredoxin interacting protein (TXNIP). Conversely, in chondrocytes derived from mice with cartilage specific Sirt6 knockout, Sirt6 loss decreased Prx1 levels and increased TXNIP levels. SIRT6 overexpression decreased nuclear-generated H2O2 levels and oxidative stress-induced accumulation of nuclear phosphorylated p65. Our data demonstrate that SIRT6 activity is altered with age and oxidative stress conditions associated with aging. SIRT6 contributes to chondrocyte redox homeostasis by regulating specific members of the Prx catalytic cycle. Targeted therapies aimed at preventing the age-related decline in SIRT6 activity may represent a novel strategy to maintain redox balance in joint tissues and decrease catabolic signaling events implicated in osteoarthritis (OA).
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影响因子：
7.4
作者：
Hu, Shugun;Liu, Hua;Ha, Yonju;Luo, Xuemei;Motamedi, Massoud;Gupta, Mahesh P.;Ma, Jian-Xing;Tilton, Ronald G.;Zhang, Wenbo
通讯作者：
Zhang, Wenbo
影响因子：
9
作者：
Iachettini S;Trisciuoglio D;Rotili D;Lucidi A;Salvati E;Zizza P;Di Leo L;Del Bufalo D;Ciriolo MR;Leonetti C;Steegborn C;Mai A;Rizzo A;Biroccio A
通讯作者：
Biroccio A
影响因子：
13.8
作者：
Kugel, Site;Mostoslavsky, Raul
通讯作者：
Mostoslavsky, Raul
影响因子：
--
作者：
Klomsiri, Chananat;Nelson, Kimberly J.;Bechtold, Erika;Soito, Laura;Johnson, Lynnette C.;Lowther, W. Todd;Ryu, Seong-Eon;King, S. Bruce;Furdui, Cristina M.;Poole, Leslie B.
通讯作者：
Poole, Leslie B.
小鼠生长板软骨细胞中 PI3K 基因表达的调节。
影响因子：
3.7
作者：
Ulici, Veronica;James, Claudine G.;Hoenselaar, Katie D.;Beier, Frank
通讯作者：
Beier, Frank