Bmi-1-RING1B prevents GATA4-dependent senescence-associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4.
Bmi-1-RING1B prevents GATA4-dependent senescence-associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4.
复制标题
Bmi-1-RING1B 通过促进 GATA4 的自噬降解来预防 GATA4 依赖性衰老相关的病理性心脏肥大
DOI：
10.1002/ctm2.574
复制
发表时间：
2022-04
影响因子：
10.6
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Chen H;Zhou J;Chen H;Liang J;Xie C;Gu X;Wang R;Mao Z;Zhang Y;Li Q;Zuo G;Miao D;Jin J
衰老相关病理性心脏肥大（SA-PCH）与胎儿基因上调、纤维化、衰老相关分泌表型（SASP）、心功能不全以及发病率和死亡率增加有关。因此，我们进行了实验来研究GATA4积累是否会诱导SA-PCH，以及Bmi-1-RING1B是否促进GATA4泛素化及其选择性自噬降解以预防SA-PCH。 Bmi-1 缺陷 (Bmi-1−/− )、转基因 Bmi-1 过表达 (Bmi-1Tg ) 和野生型 (WT) 小鼠被注射血管紧张素 II (Ang II) 以刺激 SA-PCH 的发育。通过对心脏组织RNA测序数据进行生物信息学分析，我们发现Bmi-1-RING1B和自噬与SA-PCH呈负相关。 Bmi-1缺陷通过增加GATA4蛋白和GATA4转录的肥大相关分子（例如ANP和BNP）来促进GATA4依赖性SA-PCH。 Bmi-1 缺乏会刺激 NF-κB-p65 依赖性 SASP，导致心功能障碍、心肌细胞肥大和衰老。 Bmi-1 过表达抑制 GATA4 依赖性 SA-PCH。 Bmi-1对GATA4的降解主要依赖于自噬而非蛋白酶体。在人心肌中，p16与ANP和GATA4呈正相关，与LC3B、Bmi-1和RING1B呈负相关； GATA4 与 p62 呈正相关，与 Bmi-1 和 LC3B 呈负相关。随着 p16 蛋白水平的增加，ANP、BNP 和 GATA4 阳性细胞或区域增加；然而，人类心肌中 LC3B 阳性细胞或面积减少。 GATA4与Bmi-1-RING1B结合后泛素化，被p62识别，易位至自噬体形成自噬溶酶体并被降解。下调 GATA4 通过减少 GATA4 依赖性肥大和 SASP 相关分子来改善 SA-PCH 和心脏功能障碍。 Bmi-1 通过残基 1-95（包括 RING-HC 指）与 RING1B（残基 1-179）和 GATA4（残基 206-443，包括锌指结构域）的 C 末端结合。 RING1B 通过 C 末端（残基 180-336）与 GATA4 的 C 末端结合。腺相关病毒载体血清型 9 (AAV9)-巨细胞病毒 (CMV)-Bmi-1-RING1B 治疗通过促进 GATA4 自噬降解显着减弱 GATA4 依赖性 SA-PCH。 Bmi-1-RING1B 通过促进选择性自噬降解 GATA4 来维持心脏功能并预防 SA-PCH。 AAV9-CMV-Bmi-1-RING1B 可用于翻译基因治疗，以泛素化 GATA4 并预防 GATA4 依赖性 SA-PCH。此外，衰老心肌细胞中 Bmi-1-RING1B 和 GATA4 之间的组合结构域可以作为临床应用中鉴定钉合肽的治疗靶点，以促进 Bmi-1-RING1B 与 GATA4 的结合以及 GATA4 的泛素化，从而预防 SA-PCH 和心力衰竭。我们发现Bmi-1对心脏GATA4的降解主要依赖于自噬而不是蛋白酶体，自噬激动剂二甲双胍和雷帕霉素可以改善SA-PCH，这表明用二甲双胍或雷帕霉素激活自噬也可能是预防SA-PCH的有前途的方法。 GATA4与Bmi-1-RING1B结合后被泛素化，然后被p62识别，易位至自噬体形成自噬溶酶体并被降解。下调 GATA4 通过减少 GATA4 依赖性肥大和 SASP 相关分子来改善 SA-PCH 和心脏功能障碍。 Bmi-1 通过残基 1-95（包括 RING-HC 指）与 RING1B（残基 1-179）和 GATA4（残基 206 至 443 的 C 末端，包括锌指结构域）结合。 RING1B 通过 C 末端（残基 180-336）与 GATA4（残基 206 至 443 的 C 末端，包括锌指结构域）结合。 AAV9-CMV-Bmi-1-RING1B 用于基因治疗以预防 GATA4 依赖性 SA-PCH。 Bmi-1-RING1B 和 GATA4 之间的组合结构域可以作为识别钉合肽以促进它们组合的治疗靶点。
Senescence‐associated pathological cardiac hypertrophy (SA‐PCH) is associated with upregulation of foetal genes, fibrosis, senescence‐associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA‐PCH, and whether Bmi‐1‐RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA‐PCH. Bmi‐1‐deficient (Bmi‐1−/− ), transgenic Bmi‐1 overexpressing (Bmi‐1Tg ) and wild‐type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA‐PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi‐1‐RING1B and autophagy are negatively related to SA‐PCH. Bmi‐1 deficiency promoted GATA4‐dependent SA‐PCH by increasing GATA4 protein and hypertrophy‐related molecules transcribed by GATA4 such as ANP and BNP. Bmi‐1 deficiency stimulated NF‐κB‐p65‐dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi‐1 overexpression repressed GATA4‐dependent SA‐PCH. GATA4 degraded by Bmi‐1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi‐1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi‐1 and LC3B. With increased p16 protein levels, ANP‐, BNP‐ and GATA4‐positive cells or areas increased; however, LC3B‐positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi‐1‐RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA‐PCH and cardiac dysfunction by reducing GATA4‐dependent hypertrophy and SASP‐related molecules. Bmi‐1 combined with RING1B (residues 1–179) and C‐terminus of GATA4 (residues 206–443 including zinc finger domains) through residues 1–95, including a RING‐HC‐finger. RING1B combined with C‐terminus of GATA4 through the C‐terminus (residues 180–336). Adeno‐associated viral vector serotype 9 (AAV9)‐cytomegalovirus (CMV)‐Bmi‐1‐RING1B treatment significantly attenuated GATA4‐dependent SA‐PCH through promoting GATA4 autophagic degradation. Bmi‐1‐RING1B maintained cardiac function and prevented SA‐PCH by promoting selective autophagy for degrading GATA4. AAV9‐CMV‐Bmi‐1‐RING1B could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4‐dependent SA‐PCH. Also, the combined domains between Bmi‐1‐RING1B and GATA4 in aging cardiomyocytes could be therapeutic targets for identifying stapled peptides in clinical applications to promote the combination of Bmi‐1‐RING1B with GATA4 and the ubiquitination of GATA4 to prevent SA‐PCH and heart failure. We found that degradation of cardiac GATA4 by Bmi‐1 was mainly dependent on autophagy rather than proteasome, and autophagy agonists metformin and rapamycin could ameliorate the SA‐PCH, suggesting that activation of autophagy with metformin or rapamycin could also be a promising method to prevent SA‐PCH. GATA4 is ubiquitinated after combining with Bmi‐1‐RING1B, which is then recognized by p62, translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA‐PCH and cardiac dysfunction by reducing GATA4‐dependent hypertrophy and SASP‐related molecules. Bmi‐1 combined with RING1B (residues 1‐179) and GATA4 (C‐terminus from residues 206 to 443 including zinc finger domains) through residues 1‐95 including a RING‐HC‐finger. RING1B combined with GATA4 (C‐terminus from residues 206 to 443 including zinc finger domains) through the C‐terminus (residues 180‐336). AAV9‐CMV‐Bmi‐1‐RING1B is used for gene therapy to prevent GATA4‐dependent SA‐PCH. The combined domains between Bmi‐1‐RING1B and GATA4 could be therapeutic targets for identifying stapled peptides to promote the combination of them.
登录
查看更多内容
伴侣介导的自噬的时代的到来。
DOI：
10.1038/s41580-018-0001-6
发表时间：
2018-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Kaushik S;Cuervo AM
通讯作者：
Cuervo AM
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
氧化应激通过 Gata4 转录和蛋白泛素化对心肌生成的硬脑膜影响
影响因子：
9
作者：
Li T;Zhang X;Jiang K;Liu J;Liu Z
通讯作者：
Liu Z
影响因子：
37.8
作者：
Jessup M;Greenberg B;Mancini D;Cappola T;Pauly DF;Jaski B;Yaroshinsky A;Zsebo KM;Dittrich H;Hajjar RJ;Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
通讯作者：
Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
影响因子：
11.4
作者：
Buchwald, Gretel;van der Stoop, Petra;Sixma, Titia K.
通讯作者：
Sixma, Titia K.