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

Lachowicz, Joanna I.; Pichiri, Giusi; Piludu, Marco; Fais, Sara; Orrù, Germano; Congiu, Terenzio; Piras, Monica; Faa, Gavino; Fanni, Daniela; Dalla Torre, Gabriele; Lopez, Xabier; Chandra, Kousik; Szczepski, Kacper; Jaremko, Lukasz; Ghosh, Mitra; Emwas, Abdul-Hamid; Castagnola, Massimo; Jaremko, Mariusz; Hannappel, Ewald; Coni, Pierpaolo

doi:10.3390/ijms23010551

Open AccessArticle

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

by

Joanna I. Lachowicz

¹

,

Giusi Pichiri

^1,*,

Marco Piludu

^2,*,

Sara Fais

³,

Germano Orrù

³,

Terenzio Congiu

¹,

Monica Piras

¹,

Gavino Faa

¹

,

Daniela Fanni

¹,

Gabriele Dalla Torre

⁴

,

Xabier Lopez

⁴,

Kousik Chandra

⁵,

Kacper Szczepski

⁵,

Lukasz Jaremko

⁵

,

Mitra Ghosh

⁵,

Abdul-Hamid Emwas

⁶,

Massimo Castagnola

^7,8,

Mariusz Jaremko

^5,*,

Ewald Hannappel

⁹

and

Pierpaolo Coni

¹

Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy

²

Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy

³

Department of Surgical Science, OBL Oral Biotechnology Laboratory, University of Cagliari, 09124 Cagliari, Italy

⁴

Kimika Fakultatea, Euskal Herriko Unibertsitatea UPV/EHU, Donostia International Physics Center (DIPC), P.K. 1072 Donostia Euskadi, 20080 San Sebastian, Spain

⁵

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

⁶

Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia

⁷

Institute of Chemistry of Molecular Recognition, National Research Council (Consiglio Nazionale delle Ricerche), 00185 Rome, Italy

⁸

Laboratory of Proteomics and Metabolomics, IRCCS, Santa Lucia Foundation, 00143 Rome, Italy

⁹

Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nuremberg, 91058 Erlangen, Germany

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(1), 551; https://doi.org/10.3390/ijms23010551

Submission received: 13 December 2021 / Revised: 1 January 2022 / Accepted: 3 January 2022 / Published: 4 January 2022

(This article belongs to the Section Biochemistry)

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Abstract

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.

Keywords: thymosine beta 4; ferroptosis; metal chelation; TEM; mRNA; molecular dynamics; NMR

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MDPI and ACS Style

Lachowicz, J.I.; Pichiri, G.; Piludu, M.; Fais, S.; Orrù, G.; Congiu, T.; Piras, M.; Faa, G.; Fanni, D.; Dalla Torre, G.; et al. Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis. Int. J. Mol. Sci. 2022, 23, 551. https://doi.org/10.3390/ijms23010551

AMA Style

Lachowicz JI, Pichiri G, Piludu M, Fais S, Orrù G, Congiu T, Piras M, Faa G, Fanni D, Dalla Torre G, et al. Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis. International Journal of Molecular Sciences. 2022; 23(1):551. https://doi.org/10.3390/ijms23010551

Chicago/Turabian Style

Lachowicz, Joanna I., Giusi Pichiri, Marco Piludu, Sara Fais, Germano Orrù, Terenzio Congiu, Monica Piras, Gavino Faa, Daniela Fanni, Gabriele Dalla Torre, and et al. 2022. "Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis" International Journal of Molecular Sciences 23, no. 1: 551. https://doi.org/10.3390/ijms23010551

APA Style

Lachowicz, J. I., Pichiri, G., Piludu, M., Fais, S., Orrù, G., Congiu, T., Piras, M., Faa, G., Fanni, D., Dalla Torre, G., Lopez, X., Chandra, K., Szczepski, K., Jaremko, L., Ghosh, M., Emwas, A.-H., Castagnola, M., Jaremko, M., Hannappel, E., & Coni, P. (2022). Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis. International Journal of Molecular Sciences, 23(1), 551. https://doi.org/10.3390/ijms23010551

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

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