Thymosin beta 4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis

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

Research output: Contribution to journalArticlepeer-review

Abstract

Thymosin beta 4 (T beta 4) 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. T beta 4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of T beta 4 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 T beta 4 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 iron(2+) and iron(3+) binding regions along the peptide and show that the presence of T beta 4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, T beta 4 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 T beta 4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of T beta 4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled T beta 4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies.

Original languageEnglish
Article number551
Number of pages22
JournalInternational Journal of Molecular Sciences
Volume23
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • thymosine beta 4
  • ferroptosis
  • metal chelation
  • TEM
  • mRNA
  • molecular dynamics
  • NMR
  • CELL-DEATH
  • OXIDATIVE STRESS
  • HEME OXYGENASE-1
  • CANCER CELLS
  • SIDE-CHAIN
  • G-ACTIN
  • BAX
  • HOMEOSTASIS
  • ACTIVATION
  • EXPRESSION

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