Iron drives anabolic metabolism through active histone demethylation and mTORC1
Shapiro, Jason S; Chang, Hsiang-Chun; Tatekoshi, Yuki; Zhao, Zibo; Waxali, Zohra Sattar; Hong, Bong Jin; Chen, Haimei; Geier, Justin A; Bartom, Elizabeth T; De Jesus, Adam; Nejad, Farnaz K; Mahmoodzadeh, Amir; Sato, Tatsuya; Ramos-Alonso, Lucia; Romero, Antonia Maria; Martinez-Pastor, Maria Teresa; Jiang, Shang-Chuan; Sah-Teli, Shiv K; Li, Liming; Bentrem, David; Lopaschuk, Gary; Ben-Sahra, Issam; O'Halloran, Thomas V; Shilatifard, Ali; Puig, Sergi; Bergelson, Joy; Koivunen, Peppi; Ardehali, Hossein (2023-09-25)
Springer
25.09.2023
Shapiro, J.S., Chang, HC., Tatekoshi, Y. et al. Iron drives anabolic metabolism through active histone demethylation and mTORC1. Nat Cell Biol 25, 1478–1494 (2023). https://doi.org/10.1038/s41556-023-01225-6
https://rightsstatements.org/vocab/InC/1.0/
© The Author(s), under exclusive licence to Springer Nature Limited 2023. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41556-023-01225-6.
https://rightsstatements.org/vocab/InC/1.0/
© The Author(s), under exclusive licence to Springer Nature Limited 2023. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41556-023-01225-6.
https://rightsstatements.org/vocab/InC/1.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202504072440
https://urn.fi/URN:NBN:fi:oulu-202504072440
Tiivistelmä
Abstract
All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
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