Cargando…

Phase separation of FSP1 promotes ferroptosis

Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers(1–3). Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H(+) as...

Descripción completa

Detalles Bibliográficos
Autores principales: Nakamura, Toshitaka, Hipp, Clara, Santos Dias Mourão, André, Borggräfe, Jan, Aldrovandi, Maceler, Henkelmann, Bernhard, Wanninger, Jonas, Mishima, Eikan, Lytton, Elena, Emler, David, Proneth, Bettina, Sattler, Michael, Conrad, Marcus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338336/
https://www.ncbi.nlm.nih.gov/pubmed/37380771
http://dx.doi.org/10.1038/s41586-023-06255-6
_version_ 1785071606625730560
author Nakamura, Toshitaka
Hipp, Clara
Santos Dias Mourão, André
Borggräfe, Jan
Aldrovandi, Maceler
Henkelmann, Bernhard
Wanninger, Jonas
Mishima, Eikan
Lytton, Elena
Emler, David
Proneth, Bettina
Sattler, Michael
Conrad, Marcus
author_facet Nakamura, Toshitaka
Hipp, Clara
Santos Dias Mourão, André
Borggräfe, Jan
Aldrovandi, Maceler
Henkelmann, Bernhard
Wanninger, Jonas
Mishima, Eikan
Lytton, Elena
Emler, David
Proneth, Bettina
Sattler, Michael
Conrad, Marcus
author_sort Nakamura, Toshitaka
collection PubMed
description Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers(1–3). Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H(+) as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis(4–6). To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor(5), does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity(7). N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.
format Online
Article
Text
id pubmed-10338336
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-103383362023-07-14 Phase separation of FSP1 promotes ferroptosis Nakamura, Toshitaka Hipp, Clara Santos Dias Mourão, André Borggräfe, Jan Aldrovandi, Maceler Henkelmann, Bernhard Wanninger, Jonas Mishima, Eikan Lytton, Elena Emler, David Proneth, Bettina Sattler, Michael Conrad, Marcus Nature Article Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers(1–3). Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H(+) as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis(4–6). To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor(5), does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity(7). N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy. Nature Publishing Group UK 2023-06-28 2023 /pmc/articles/PMC10338336/ /pubmed/37380771 http://dx.doi.org/10.1038/s41586-023-06255-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Nakamura, Toshitaka
Hipp, Clara
Santos Dias Mourão, André
Borggräfe, Jan
Aldrovandi, Maceler
Henkelmann, Bernhard
Wanninger, Jonas
Mishima, Eikan
Lytton, Elena
Emler, David
Proneth, Bettina
Sattler, Michael
Conrad, Marcus
Phase separation of FSP1 promotes ferroptosis
title Phase separation of FSP1 promotes ferroptosis
title_full Phase separation of FSP1 promotes ferroptosis
title_fullStr Phase separation of FSP1 promotes ferroptosis
title_full_unstemmed Phase separation of FSP1 promotes ferroptosis
title_short Phase separation of FSP1 promotes ferroptosis
title_sort phase separation of fsp1 promotes ferroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338336/
https://www.ncbi.nlm.nih.gov/pubmed/37380771
http://dx.doi.org/10.1038/s41586-023-06255-6
work_keys_str_mv AT nakamuratoshitaka phaseseparationoffsp1promotesferroptosis
AT hippclara phaseseparationoffsp1promotesferroptosis
AT santosdiasmouraoandre phaseseparationoffsp1promotesferroptosis
AT borggrafejan phaseseparationoffsp1promotesferroptosis
AT aldrovandimaceler phaseseparationoffsp1promotesferroptosis
AT henkelmannbernhard phaseseparationoffsp1promotesferroptosis
AT wanningerjonas phaseseparationoffsp1promotesferroptosis
AT mishimaeikan phaseseparationoffsp1promotesferroptosis
AT lyttonelena phaseseparationoffsp1promotesferroptosis
AT emlerdavid phaseseparationoffsp1promotesferroptosis
AT pronethbettina phaseseparationoffsp1promotesferroptosis
AT sattlermichael phaseseparationoffsp1promotesferroptosis
AT conradmarcus phaseseparationoffsp1promotesferroptosis