Ncl liquid-liquid phase separation and SUMOylation mediate the stabilization of HIF-1α expression and promote pyroptosis in ischemic hindlimb
Year: 2025
Type: article
Abstract: Liquid-liquid phase separation (LLPS) has emerged as a flexible intracellular compartment that modulates various pathological processes. Hypoxia-inducible factor-1α (HIF-1α) has been shown to play an essential role in inflammation after ischemic injury. However, the mechanisms underlying HIF-1α-induced inflammation in ischemic diseases have not been defined. This study found that HIF-1α mediated the progression of ischemia-induced muscle injury. After ischemic injury, SUMO1 is upregulated and rapidly activates NLRP3 inflammasome through the upregulation of HIF-1α, leading to enhanced inflammation and pyroptosis. Co-IP revealed an interaction between SUMO1 and HIF-1α and SUMOylation of HIF-1α at K477. Moreover, we demonstrated the important role of dynamic phase separation of Nucleolin (Ncl) in regulating HIF-1α mRNA stability through fluorescence recovery after photobleach (FRAP) analysis. The stability of HIF-1α is regulated by Ncl liquid-liquid phase separation and SUMOylation in ischemia-induced hindlimb injury. HIF-1α can promote the expression of NLRP3 and other inflammation-related molecules, leading to pyroptosis, suggesting that Ncl/LLPS/HIF-1α or SUMO1/HIF-1α pathway may be a new target for the treatment of inflammation in ischemic diseases. Although previous studies have found that HIF-1α is able to promote the expression of target genes after hypoxia, and these genes are used to maintain the stability of the intracellular environment to adapt to hypoxia. We found that HIF-1α is involved in the activation process of NLRP3 inflammasomes after hind limb ischemia, which enriches our understanding of the biological role of HIF-1α. • The specific mechanisms of NLRP3 inflammasome and pyroptosis induced dysfunction of skeletal muscles are unclear. • Ncl regulates the stability of HIF-1α mRNA through liquid-liquid phase separation. • SUMOylation of HIF-1α at K477 by SUMO1 enhances its stability. • The inhibition of HIF-1α prevents inflammation and pyroptosis during muscle injury.
Authors: Yanli Wang, Weiliang Wu, Yan Xu, Chengjie Wu, Qingfang Han, Tonggan Lu, Huiling Zhang, Lijuan Jiao, Yu Zhang, Bin Liu, Xi-yong Yu, Yangxin Li
Institutions: Soochow University, First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Central South University, Second Xiangya Hospital of Central South University, Jilin University, Second Affiliated Hospital of Jilin University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,010
OpenAlex ID: W4407345712