ELT-2 promotesO-GlcNAc transferase OGT-1 expression to modulateCaenorhabditis eleganslifespan
ELT-2 promotesO-GlcNAc transferase OGT-1 expression to modulateCaenorhabditis eleganslifespan
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ELT-2促进O-GlcNAc转移酶OGT-1表达调节线虫寿命
DOI：
10.1002/jcb.29817
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发表时间：
2020
影响因子：
4
通讯作者：
Li Xiaoxue
中科院分区：
文献类型：
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作者：
Su Liangping;Zhao Tingting;Li Hongyuan;Li Hongmei;Su Xin;Ba Xueqing;Zhang Yu;Huang Baiqu;Lu Jun;Li Xiaoxue
O - GlcNAc转移酶（OGT）是一种通过将单个leo - linked - β - N -乙酰氨基葡萄糖分子（O - GlcNAc）添加到核和细胞质靶标上催化蛋白质- glcna酰化的酶，它使用尿苷二磷酸- N -乙酰氨基葡萄糖（UDP - GlcNAc）作为供体。由于UDP - GlcNAc是营养感应己糖胺信号通路的最终产物，哺乳动物或无脊椎动物模型中过表达或敲除ogtin会影响细胞营养反应信号，并增加对慢性衰老疾病的易感性。有证据表明，老年小鼠和大鼠组织中OGT表达水平下降。然而，在衰老过程中，OGT的表达是如何被调节的仍然知之甚少。在秀丽隐杆线虫中，独有的哺乳动物OGT同源物OGT‐1对寿命控制至关重要。在这里，我们观察到随着年龄的增长，蠕虫的OGT‐1表达逐渐减少。通过“MATCH”算法和荧光素酶报告基因检测相结合的预测，GATA因子ELT‐2（人类GATA4的同源物）被确定为驱动OGT‐1表达的转录因子。染色质免疫沉淀-定量聚合酶链反应和电泳迁移率转移试验表明，ELT - 2直接结合并激活了t - 1启动子。敲除felt‐2降低了globalO‐GlcNAc修饰水平，降低了野生型蠕虫的寿命。由elt‐2RNA干扰引起的寿命缩短被ogt‐1的丧失所抵消。这些结果表明GATA因子能够激活OGT的表达，这可能有利于延长寿命和开发与衰老相关疾病的治疗方法。
O‐GlcNAc transferase (OGT) is the enzyme catalyzing proteinO‐GlcNAcylation by addition of a singleO‐linked‐β‐N‐acetylglucosamine molecule (O‐GlcNAc) to nuclear and cytoplasmic targets, and it uses uridine diphosphate‐N‐acetylglucosamine (UDP‐GlcNAc) as a donor. As UDP‐GlcNAc is the final product of the nutrient‐sensing hexosamine signaling pathway, overexpression or knockout ofogtin mammals or invertebrate models influences cellular nutrient‐response signals and increases susceptibility to chronic diseases of aging. Evidence shows that OGT expression levels decrease in tissues of older mice and rats. However, how OGT expression is modulated in the aging process remains poorly understood. InCaenorhabditis elegans, the exclusive mammalian OGT ortholog OGT‐1 is crucial for lifespan control. Here, we observe that worm OGT‐1 expression gradually reduces during aging. By combining prediction via the “MATCH” algorithm and luciferase reporter assays, GATA factor ELT‐2, the homolog of human GATA4, is identified as a transcriptional factor driving OGT‐1 expression. Chromatin immunoprecipitation‐quantitative polymerase chain reaction and electrophoretic mobility shift assays show ELT‐2 directly binds to and activates theogt‐1promoter. Knockdown ofelt‐2decreases the globalO‐GlcNAc modification level and reduces the lifespan of wild‐type worms. The reduction in lifespan caused byelt‐2RNA interference is abrogated by the loss ofogt‐1. These results imply that GATA factors are able to activate OGT expression, which could be beneficial for longevity and the development of therapeutic treatment for aging‐related diseases.