Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5.

Autor: Terzi EM; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA., Sviderskiy VO; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA., Alvarez SW; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA., Whiten GC; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.; Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA., Possemato R; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA. richard.possemato@nyulangone.org.; Laura and Isaac Perlmutter Cancer Center, New York, NY 10016, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 May 26; Vol. 7 (22). Date of Electronic Publication: 2021 May 26 (Print Publication: 2021).
DOI: 10.1126/sciadv.abg4302
Abstrakt: Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5-mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O 2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich's ataxia.
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze: MEDLINE
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