TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2.
TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2.
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TGFB-INHB/激活素信号通过抑制 MTORC2 调节年龄依赖性自噬和心脏健康。
DOI：
10.1080/15548627.2019.1704117
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发表时间：
2020-10
期刊：
影响因子：
13.3
通讯作者：
Bai H
中科院分区：
文献类型：
--
作者：
Chang K;Kang P;Liu Y;Huang K;Miao T;Sagona AP;Nezis IP;Bodmer R;Ocorr K;Bai H
心脏病相关的大自噬/自噬损伤和心脏组织稳态的丧失显著地促进了以后生活中的心血管疾病。MTOR（mechanistic target of rapamycin kinase，雷帕霉素激酶的机械靶点）信号传导是自噬、细胞内稳态和寿命的最知名的调节器。MTOR信号由两种结构和功能不同的多蛋白复合物MTOR 1和MTOR 2组成。虽然MTORC 1已被很好地表征，但MTORC 2在衰老和自噬中的作用仍然知之甚少。在这里，我们确定了TGFB-INHB/激活素信号传导作为MTORC 2的一种新型上游调节因子，以控制衰老过程中的自噬和心脏健康。使用果蝇心脏作为模型系统，我们发现心脏特异性敲低TGFB-INHB/激活素样蛋白daw诱导自噬并加重年龄相关的心脏功能障碍，包括心律失常和心动过缓。有趣的是，daw的下调激活TORC 2信号传导以调节心脏自噬。TORC2通过过表达其亚基蛋白rictor单独激活可促进自噬通量，并随着衰老保护心脏功能。相比之下，TORC 1的激活不会阻断daw敲除果蝇中的自噬诱导。最后，daw敲除或rictor过度表达在苍蝇心脏延长寿命，这表明在心脏中操纵这些途径对寿命控制具有系统性影响。因此，我们的研究发现TGFB-INHB/激活素介导的TORC 2抑制是自噬活性和心脏健康的年龄依赖性降低的新机制。缩略语：人工智能：心律失常指数; BafA1：巴弗洛霉素A1; BMP：骨形态发生蛋白; CQ：氯喹; CVD：心血管疾病; DI：舒张间期;急诊室：内质网;生命值：心动期;人力资源部：心率; MTOR：雷帕霉素激酶的机制靶点; NGS：正常山羊血清; PBST：含0.1%Triton X-100的PBS; PDPK 1：3-磷酸肌醇依赖性蛋白激酶1; RICTOR：MTOR复合物2的RPTOR非依赖性伴侣; ROI：感兴趣区域; ROUT：稳健回归和离群值去除; ROS：活性氧; R-SMAD：受体激活SMAD; SI：收缩间期; SOHA：半自动光学心跳分析; TGFB：转化生长因子β; TSC 1：TSC复合物亚单位1
Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood. Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of TGFB-INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control. Thus, our studies discover the TGFB-INHB/activin-mediated inhibition of TORC2 as a novel mechanism for age-dependent decreases in autophagic activity and cardiac health. Abbreviations: AI: arrhythmia index; BafA1: bafilomycin A1; BMP: bone morphogenetic protein; CQ: chloroquine; CVD: cardiovascular diseases; DI: diastolic interval; ER: endoplasmic reticulum; HP: heart period; HR: heart rate; MTOR: mechanistic target of rapamycin kinase; NGS: normal goat serum; PBST: PBS with 0.1% Triton X-100; PDPK1: 3-phosphoinositide dependent protein kinase 1; RICTOR: RPTOR independent companion of MTOR complex 2; ROI: region of interest; ROUT: robust regression and outlier removal; ROS: reactive oxygen species; R-SMAD: receptor-activated SMAD; SI: systolic interval; SOHA: semi-automatic optical heartbeat analysis; TGFB: transformation growth factor beta; TSC1: TSC complex subunit 1
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影响因子：
4
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