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聚硫化物和硫化物介导的PERK-eIF2α-ATF4通路的激活增加了Sestrin2的表达,并降低了甲基氧毒性

Shin Koike¹, Hideo Kimura², Yuki Ogasawara¹

¹Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.

|December 12, 2024

概括

硫化合物和聚硫化物一样,通过对PERK进行持续硫化来激活PERK-eIF2α-ATF4通路. 这条通路保护神经元细胞免受损伤,提供了对内质网膜压力和疾病的见解.

科学领域:

细胞生物学细胞生物学
转毒生物学转毒生物学
神经科学是一个神经科学.

背景情况:

细胞内膜网膜 (ER) 的压力触发了展开的蛋白质反应 (UPR).
PERK 是 UPR 中的一个关键传感器蛋白,通过氧化还原依赖的寡合化来激活.
硫在调节PERK通路中的作用及其生理影响尚不清楚.

研究的目的:

研究聚硫化物对PERK-eIF2α-ATF4通路的影响.
为了阐明PERK通过硫硫化过程的机制.
探索这个途径在神经元细胞中的细胞保护作用.

主要方法:

在非还原条件下进行西面涂抹,以评估蛋白质寡合化.
降低硫硫生成酶 (CBS,3-MST) 的作用.
带移位测试和LC-MS/MS检测硫化.
对eIF2α酸化和ATF4核积累的分析.
评估神经元细胞对甲基醇毒性的保护.

主要成果:

聚硫化物治疗促进了神经细胞中PERK和PTP1B的寡合化.
硫硫的来源是l-cysteine,它诱导了PERK的寡合化,通过击败CBS和3-MST而减少了这种寡合化.
发现多硫化物和硫化物对PTP1B和PERK进行硫化.
聚硫化物激活了PERK-eIF2α-ATF4通路,导致eIF2α酸化和ATF4核积累.
聚硫化物对依赖于Sestrin2表达的甲基酸毒性进行了保护.

结论:

通过通过多硫化物和硫化物进行持续硫化来激活PERK-eIF2α-ATF4通路的新机制被确定.
这种依赖于Sestrin2的途径激活提供了对甲基氧毒性的细胞保护.
这些发现加深了对神经元疾病中ER压力和UPR的理解,并表明了治疗潜力.

关键词:

甲基格里奥克萨尔 (Methylglyoxal) 是一种过硫化物是什么? 过硫化物是什么?聚硫化物聚硫化物这就是Sestrin2的原因.在UPR路径上.

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