Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability.
Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability.
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自噬受体p62可预防糖基化衍生的毒性并增强生存能力。
DOI：
10.1111/acel.13257
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发表时间：
2020-11
期刊：
影响因子：
7.8
通讯作者：
Taylor A
中科院分区：
文献类型：
--
作者：
Aragonès G;Dasuri K;Olukorede O;Francisco SG;Renneburg C;Kumsta C;Hansen M;Kageyama S;Komatsu M;Rowan S;Volkin J;Workman M;Yang W;Daza P;Ruano D;Dominguez-Martín H;Rodríguez-Navarro JA;Du XL;Brownlee MA;Bejarano E;Taylor A
糖尿病和代谢综合征与典型的美国高血糖饮食有关，并导致高水平的晚期糖基化终产物（AGEs）积累，特别是在衰老时。当糖或其代谢物与蛋白质反应时，AGEs形成。与无数年龄相关疾病相关，AGEs在许多组织中积累并具有细胞毒性。到目前为止，限制糖基化的努力在人体试验中失败了。因此，确定清除AGEs的系统至关重要，但此类研究很少。在这里，我们确定了AGEs是否以及如何通过自噬被清除。我们的体内小鼠和C.在elegans模型中，我们改变了蛋白水解或免疫负荷，以及在五种类型的细胞中进行的实验，揭示了超过六个标准，表明p62依赖性自噬是一种保守的途径，在AGEs的去除中起着关键作用。自噬去除AGEs的激活需要p62，阻断该途径会导致AGEs的积累和活力受损。p62的缺乏加速AGEs在可溶性和不溶性组分中的积累。p62本身经历连续失活并作为高质量种类积累。p62在视网膜色素上皮细胞中的积累通过切换到低血糖饮食而逆转。由于连续性损伤的减少与年龄相关疾病的风险降低有关，包括年龄相关性黄斑变性，心血管疾病，糖尿病，阿尔茨海默病和帕金森病，发现限制AGEs或增强p62依赖性自噬的方法提供了治疗AGEs相关病理的新的潜在治疗靶点。AGEs是由糖和蛋白质之间的非酶反应形成的有毒化合物。AGEs易于聚集。不溶性AGEs通过p62选择性自噬有效去除。AGEs的自噬清除是一个保守的途径，p62的缺失导致小鼠和蠕虫中有毒AGEs的积累。增强的自噬可保护免受糖基化衍生的损伤。p62依赖性自噬为治疗AGEs相关疾病提供了新的潜在治疗靶点。
Diabetes and metabolic syndrome are associated with the typical American high glycemia diet and result in accumulation of high levels of advanced glycation end products (AGEs), particularly upon aging. AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age‐related diseases, AGEs accumulate in many tissues and are cytotoxic. To date, efforts to limit glycation pharmacologically have failed in human trials. Thus, it is crucial to identify systems that remove AGEs, but such research is scanty. Here, we determined if and how AGEs might be cleared by autophagy. Our in vivo mouse and C. elegans models, in which we altered proteolysis or glycative burden, as well as experiments in five types of cells, revealed more than six criteria indicating that p62‐dependent autophagy is a conserved pathway that plays a critical role in the removal of AGEs. Activation of autophagic removal of AGEs requires p62, and blocking this pathway results in accumulation of AGEs and compromised viability. Deficiency of p62 accelerates accumulation of AGEs in soluble and insoluble fractions. p62 itself is subject to glycative inactivation and accumulates as high mass species. Accumulation of p62 in retinal pigment epithelium is reversed by switching to a lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age‐related diseases, including age‐related macular degeneration, cardiovascular disease, diabetes, Alzheimer's, and Parkinson's, discovery of methods to limit AGEs or enhance p62‐dependent autophagy offers novel potential therapeutic targets to treat AGEs‐related pathologies. AGEs are toxic compounds formed by non‐enzymatic reactions between sugars and proteins. AGEs are prone to aggregate. Insoluble AGEs are efficiently removed via p62‐selective autophagy. The autophagic removal of AGEs is a conserved pathway, and the lack of p62 leads to accumulation of toxic AGEs in mouse and worms. Enhanced autophagy is protective against glycation‐derived damage. p62‐dependent autophagy offers novel potential therapeutic targets to treat AGEs‐related pathologies.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
3.8
作者：
Ji CH;Kwon YT
通讯作者：
Kwon YT
影响因子：
7.8
作者：
Golegaonkar S;Tabrez SS;Pandit A;Sethurathinam S;Jagadeeshaprasad MG;Bansode S;Sampathkumar SG;Kulkarni MJ;Mukhopadhyay A
通讯作者：
Mukhopadhyay A
影响因子：
7.8
作者：
Flynn JM;O'Leary MN;Zambataro CA;Academia EC;Presley MP;Garrett BJ;Zykovich A;Mooney SD;Strong R;Rosen CJ;Kapahi P;Nelson MD;Kennedy BK;Melov S
通讯作者：
Melov S
影响因子：
3.4
作者：
Bejarano E;Taylor A
通讯作者：
Taylor A