Nature cell biology · 2023
Iron drives anabolic metabolism through active histone demethylation and mTORC1.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.