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通过ULK1对相分离的p62体的酸化激活了氧化还原独立应激反应
Ryo Ikeda1,2, Daisuke Noshiro3, Hideaki Morishita1
1Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
The EMBO journal
|June 12, 2023
概括
蛋白质ULK1酸化p62,激活转录因子NRF2,而不依赖于氧化还原信号. 这种酸化导致小鼠的生长迟缓,突显了这种途径的生理重要性.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 核因子红色素2相关因子2 (NRF2) 调节抗氧化反应,通常通过氧化还原依赖机制.
- 通过液-液相分离形成的p62体,参与通过Ser349-phosphorylated p62通过NRF2的氧化还原独立激活.
- 精确的调节机制和p62酸化的生理作用尚未完全理解.
研究的目的:
- 为了确定负责p62酸化的激酶.
- 阐明p62酸化激活NRF2.2的机制.
- 为了研究氧化还原独立NRF2激活途径的生理意义.
主要方法:
- 鉴定ULK1作为p62酸化的激酶.
- 在ULK1和p62之间进行同局部化和相互作用研究.
- 产生和分析相仿 (p62S351E/+) 和缺陷 (p62S351A/S351A) 的小鼠模型.
- 敲进小鼠的表型分析,包括生长,营养状况和食道/胃道形态.
主要成果:
- ULK1直接与p62相互作用,并在Ser351.1上酸化p62.
- 依赖ULK1的p62酸化促进了KEAP1在p62体内的保留,从而导致NRF2的激活.
- 相仿性小鼠 (p62S351E/+) 显示NRF2过度激活和增长迟缓,这是由于食道和前胃阻塞引起的超化.
- 缺陷小鼠 (p62S351A/S351A) 不表现出这些表型.
结论:
- ULK1是通过p62酸化调解脱氧独立NRF2激活的关键激酶.
- p62酸化在调节NRF2活性和预防诸如皮质炎之类的病理状况方面起着至关重要的生理作用.
- 这些发现强调了相分离在NRF2通路调节中的重要性.
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