Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis

International Journal of Molecular Sciences

Abdul-Hamid Emwas¹  Marco Piludu²  Terenzio Congiu³  Daniela Fanni³  Pierpaolo Coni³  Gavino Faa³  Monica Piras³  Giusi Pichiri³  Joanna I. Lachowicz³  Germano Orrù⁴  Sara Fais⁴  Ewald Hannappel⁵  Massimo Castagnola⁶  Gabriele Dalla Torre⁷  Xabier Lopez⁷  Lukasz Jaremko⁸  Mitra Ghosh⁸  Kacper Szczepski⁸  Mariusz Jaremko⁸  Kousik Chandra⁸ 

[1] Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia;Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy;Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy;Department of Surgical Science, OBL Oral Biotechnology Laboratory, University of Cagliari, 09124 Cagliari, Italy;Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nuremberg, 91058 Erlangen, Germany;Institute of Chemistry of Molecular Recognition, National Research Council (Consiglio Nazionale delle Ricerche), 00185 Rome, Italy;Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, Donostia International Physics Center (DIPC), P.K. 1072 Donostia Euskadi, 20080 San Sebastian, Spain;Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia;

关键词: thymosine beta 4;    ferroptosis;    metal chelation;    TEM;    mRNA;    molecular dynamics;   

DOI  :  10.3390/ijms23010551

来源: DOAJ

【 摘 要 】

Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron²⁺ and iron³⁺ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.

【 授权许可】

Unknown