2. Academic Validation
  3. PGAM5 promotes RIPK1-PANoptosome activity by phosphorylating and activating RIPK1 to mediate PANoptosis after subarachnoid hemorrhage in rats

PGAM5 promotes RIPK1-PANoptosome activity by phosphorylating and activating RIPK1 to mediate PANoptosis after subarachnoid hemorrhage in rats

  • Exp Neurol. 2025 Feb:384:115072. doi: 10.1016/j.expneurol.2024.115072.
Duan Jiajia 1,  Yuan Wen 2,  Jiang Enyan 1,  Zhang Xiaojian 1,  Fang Zhen 1,  Zeng Jia 1,  Wang Jikai 1,  Yan Xiaoxin 3,  Liu Aihua 4,  Kong Fangen 5,  Liu Fei 6
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
  • 2 Department of Neurosurgery, Zhuzhou Central Hospital, Zhuzhou, Hunan 412000, China.
  • 3 Department of Anatomy and Neurobiology, Xiangya Medicine School, Central South University, Changsha, Hunan, China.
  • 4 Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 5 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China. Electronic address: kongfg@mail.sysu.edu.cn.
  • 6 Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China. Electronic address: liuf235@mail.sysu.edu.cn.
PMID: 39603487 DOI: 10.1016/j.expneurol.2024.115072
Abstract

Neuronal death plays a crucial role in early brain injury after subarachnoid hemorrhage (SAH). PANoptosis is a programmed form of cell death regulated by the PANoptosome, which possesses key characteristics of Pyroptosis, Apoptosis and Necroptosis. Phosphoglycerate mutase family member 5 (PGAM5) has specific Phosphatase activity that phosphorylates or dephosphorylates serine and threonine residues on bound proteins such as receptor-interacting protein kinase 1 (RIPK1), which are involved in programmed cell death. This study aimed to explore whether PANoptosis occurs after subarachnoid hemorrhage and to investigate the role of PGAM5 in early brain injury after SAH. A monofilament perforation SAH model in Sprague-Dawley rats was established, and PGAM5 siRNA (siPGAM5) was administered via intracerebroventricular injection 48 h before SAH modeling. The efficacy of siPGAM5 treatment was assessed via neurological scoring, and the impact of siPGAM5 on PANoptosis was evaluated via Western blotting, TUNEL staining and ELISA. To investigate its potential mechanism, the RIPK1 Activator birinapant was administered intraperitoneally 0.5 h after SAH. The role of RIPK in PGAM5-mediated PANoptosis was evaluated by Western blotting and coimmunoprecipitation. Our findings indicate that PANoptosis occurs in neurons after SAH and that reducing PGAM5 in the cytosol after SAH can reduce PANoptosis and enhance the short-term and long-term neurological functions of SAH rats. Mechanistically, we discovered that PGAM5 can directly bind to and phosphorylate and activate RIPK1 (ser 166), triggering the assembly of the RIPK1-PANoptosome complex. In conclusion, our study revealed that the increased PGAM5 in the mitochondria-free cytosol after SAH can bind to and activate RIPK1 (ser 166), driving the assembly of the RIPK1-PANoptosome and mediating PANoptosis after SAH. PGAM5 and PANoptosis might be novel therapeutic targets for SAH.

Keywords

Early brain injury; Experimental subarachnoid hemorrhage; PANoptosis; PGAM5; RIPK1-PANoptosome.

Figures
Products