Rapamycin relieves the cataract caused by ablation of Gja8b through stimulating autophagy in zebrafish.
Rapamycin relieves the cataract caused by ablation of Gja8b through stimulating autophagy in zebrafish.
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雷帕霉素通过刺激斑马鱼自噬缓解 Gja8b 消融引起的白内障
DOI：
10.1080/15548627.2021.1872188
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发表时间：
2021-11
期刊：
影响因子：
13.3
通讯作者：
Shentu X
中科院分区：
文献类型：
--
作者：
Ping X;Liang J;Shi K;Bao J;Wu J;Yu X;Tang X;Zou J;Shentu X
已知宏自噬/自噬对于晶状体细胞内质量控制很重要。GJA8是脊椎动物晶状体中主要的缝隙连接蛋白。GJA8基因突变会导致人类白内障。众所周知的白内障发生机制是，突变的GJA8导致缝隙连接的异常组装，导致晶状体细胞之间的细胞间通讯缺陷。在这项研究中，我们观察到在斑马鱼中消融Gja8b(哺乳动物GJA8的同源物)导致细胞器降解的严重缺陷，这是发育中晶状体发生白内障的重要原因。自噬在晶状体细胞器降解中的作用仍然存在争议。有趣的是，我们还观察到，Gja8b的消融导致了晶状体中存在缺陷的自噬。更重要的是，用雷帕霉素(一种抑制MAPK/JNK和mTORC1信号的自噬激活剂)在体内处理斑马鱼，刺激了晶状体的自噬，缓解了细胞器降解的缺陷，从而减轻了gja8b突变斑马鱼的白内障。相反，化学试剂3-MA对自噬的抑制作用阻断了这些恢复效应，这表明自噬在gja8b突变斑马鱼晶状体细胞器降解中起着重要作用。在HLE细胞中的进一步研究表明，GJA8与ATG蛋白相互作用。过表达GJA8可诱导HLE细胞自噬。这些数据表明，Gja8b的消融导致了一种未知的白内障发生机制，并可能通过刺激晶状体中的自噬来治疗白内障。缩写：3-MA：3-甲基腺嘌呤；ATG：自噬相关；AV：自噬空泡；DPF：受精后数天；GJA1：缝隙连接蛋白α1；GJA3：缝隙连接蛋白α3；GJA8：缝隙连接蛋白α8；HPF：受精后数小时；MAP1LC3/LC3：微管相关蛋白1轻链3；MTOR：雷帕霉素激酶的机械靶点；PtdIns3K：III类磷脂酰肌醇3-激酶；WT：野生型。
Macroautophagy/autophagy is known to be important for intracellular quality control in the lens. GJA8 is a major gap junction protein in vertebrate lenses. Mutations in GJA8 cause cataracts in humans. The well-known cataractogenesis mechanism is that mutated GJA8 leads to abnormal assembly of gap junctions, resulting in defects in intercellular communication among lens cells. In this study, we observed that ablation of Gja8b (a homolog of mammalian GJA8) in zebrafish led to severe defects in organelle degradation, an important cause of cataractogenesis in developing lens. The role of autophagy in organelle degradation in lens remains disputable. Intriguingly, we also observed that ablation of Gja8b induced deficient autophagy in the lens. More importantly, in vivo treatment of zebrafish with rapamycin, an autophagy activator that inhibits MAPK/JNK and MTORC1 signaling, stimulated autophagy in the lens and relieved the defects in organelle degradation, resulting in the mitigation of cataracts in gja8b mutant zebrafish. Conversely, inhibition of autophagy by treatment with the chemical reagent 3-MA blocked these recovery effects, suggesting the important roles of autophagy in organelle degradation in the lens in gja8b mutant zebrafish. Further studies in HLE cells revealed that GJA8 interacted with ATG proteins. Overexpression of GJA8 stimulated autophagy in HLE cells. These data suggest an unrecognized cataractogenesis mechanism caused by ablation of Gja8b and a potential treatment for cataracts by stimulating autophagy in the lens. Abbreviations: 3-MA: 3-methyladenine; ATG: autophagy related; AV: autophagic vacuoles; Dpf: days post fertilization; GJA1: gap junction protein alpha 1; GJA3: gap junction protein alpha 3; GJA8: gap junction protein alpha 8; Hpf: hours post fertilization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; WT: wild type.
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影响因子：
64.5
作者：
Gong, XH;Li, E;Gilula, NB
通讯作者：
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影响因子：
3.4
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