Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA.
Nat Commun. 2023 Jul 28;14(1):4543. doi: 10.1038/s41467-023-40317-7.
The conserved p38 MAPK family is activated by phosphorylation during stress responses and inactivated by phosphatases. C. elegans PMK-1 p38 MAPK initiates innate immune responses and blocks development when hyperactivated. Here we show that PMK-1 signaling is enhanced during early aging by modulating the stoichiometry of non-phospho-PMK-1 to promote tissue integrity and longevity. Loss of pmk-1 function accelerates progressive declines in neuronal integrity and lysosome function compromising longevity which has both cell autonomous and cell non-autonomous contributions. CED-3 caspase cleavage limits phosphorylated PMK-1. Enhancing p38 signaling with caspase cleavage-resistant PMK-1 protects lysosomal and neuronal integrity extending a youthful phase. PMK-1 works through a complex transcriptional program to regulate lysosome formation. During early aging, the absolute phospho-p38 amount is maintained but the reservoir of non-phospho-p38 diminishes to enhance signaling without hyperactivation. Our findings show that modulating the stoichiometry of non-phospho-p38 dynamically supports tissue-homeostasis during aging without hyper-activation of stress response.
p38 MAPK 家族在应激反应中通过磷酸化激活，在去磷酸化酶的作用下失活。秀丽隐杆线虫 PMK-1 p38 MAPK 在过度激活时会引发先天免疫反应并阻止发育。本文研究表明，PMK-1 信号在早期衰老过程中通过调节非磷酸化 PMK-1 的比例来增强，以促进组织完整性和寿命。pmk-1 功能丧失会加速神经元完整性和溶酶体功能的逐渐下降，从而缩短寿命，这既有细胞自主的贡献，也有细胞非自主的贡献。CED-3 半胱天冬酶切割限制磷酸化 PMK-1。用对半胱天冬酶切割有抗性的 PMK-1 增强 p38 信号可保护溶酶体和神经元的完整性，延长年轻阶段。PMK-1 通过一个复杂的转录程序来调节溶酶体的形成。在早期衰老过程中，绝对磷酸化 p38 的数量保持不变，但非磷酸化 p38 的储备减少，从而增强信号而不导致过度激活。研究结果表明，通过动态调节非磷酸化 p38 的化学计量，在不引起应激反应过度激活的情况下，支持衰老过程中的组织稳态。
