CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function.
CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function.
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CIB2调节mTORC1信号，对自噬和视觉功能是必不可少的。
DOI：
10.1038/s41467-021-24056-1
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发表时间：
2021-06-23
影响因子：
16.6
通讯作者：
Ahmed ZM
中科院分区：
文献类型：
--
作者：
Sethna S;Scott PA;Giese APJ;Duncan T;Jian X;Riazuddin S;Randazzo PA;Redmond TM;Bernstein SL;Riazuddin S;Ahmed ZM
视网膜相关性黄斑变性（AMD）是一种多因素的神经退行性疾病。虽然分子机制仍然难以捉摸，但自噬缺陷与AMD相关。在这里，我们表明，小鼠中钙和整合素结合蛋白2（CIB 2）的缺乏导致年龄相关的病理学，包括视网膜下色素上皮（RPE）沉积，玻璃疣标志物APOE，C3，Aβ和酯化胆固醇的显著积累，以及视觉功能受损，可以使用外源性类维生素A来挽救。Cib 2突变小鼠表现出降低的溶酶体能力和自噬清除，并增加mTORC 1信号-自噬的负调节。我们在干AMD RPE/脉络膜死后人体组织中观察到一致的分子缺陷。CIB 2通过优先结合“核苷酸空”或无活性的GDP负载的Rheb来负调节mTORC 1。上调的mTORC 1信号转导与淋巴管平滑肌瘤病（LAM）癌症有关。在LAM患者来源的成纤维细胞中过表达CIB 2下调过度活跃的mTORC 1信号传导。因此，我们的研究结果对AMD和其他mTORC 1多动相关疾病的治疗具有重要意义。视网膜相关性黄斑变性（AMD）与自噬缺陷有关。在这里，作者证明，在小鼠和干性AMD患者样本中，钙和整合素结合蛋白2（CIB 2）调节Rheb-mTORC 1信号传导轴，随后是自噬。
Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders. Age-related macular degeneration (AMD) has been connected to deficits in autophagy. Here, the authors demonstrate, in mice and dry-AMD patient samples, that calcium and integrin binding protein 2 (CIB2) regulates Rheb-mTORC1 signaling axis, and subsequently autophagy.
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影响因子：
64.5
作者：
Kim JY;Zhao H;Martinez J;Doggett TA;Kolesnikov AV;Tang PH;Ablonczy Z;Chan CC;Zhou Z;Green DR;Ferguson TA
通讯作者：
Ferguson TA
影响因子：
16.6
作者：
Giese APJ;Tang YQ;Sinha GP;Bowl MR;Goldring AC;Parker A;Freeman MJ;Brown SDM;Riazuddin S;Fettiplace R;Schafer WR;Frolenkov GI;Ahmed ZM
通讯作者：
Ahmed ZM
影响因子：
5.3
作者：
Li, Y;Inoki, K;Guan, KL
通讯作者：
Guan, KL
AMPK：代谢和线粒体稳态的监护人。
DOI：
10.1038/nrm.2017.95
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Herzig S;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
3.3
作者：
Bird, Jonathan E.;Barzik, Melanie;Friedman, Thomas B.
通讯作者：
Friedman, Thomas B.