title: Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2.
abstract: SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels. The reduction in nuclear NRF2 leads to reduced ferroportin 1 (FPN1) expression, which in turn results in decreased cellular iron export. Finally, we observed that Sirt2 deletion reduced cell viability in response to iron deficiency. Moreover, livers from Sirt2-/- mice had decreased iron levels, while this effect was reversed in Sirt2-/- Nrf2-/- double-KO mice. Taken together, our results uncover a link between sirtuin proteins and direct control over cellular iron homeostasis via regulation of NRF2 deacetylation and stability.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yang
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chang
authors.forename: Jason S
authors.initials: JS
authors.lastname: Shapiro
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.forename: Konrad T
authors.initials: KT
authors.lastname: Sawicki
authors.forename: Chunlei
authors.initials: C
authors.lastname: Chen
authors.forename: Meng
authors.initials: M
authors.lastname: Shang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Burridge
authors.forename: Conrad L
authors.initials: CL
authors.lastname: Epting
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Wilsbacher
authors.forename: Supak
authors.initials: S
authors.lastname: Jenkitkasemwong
authors.forename: Mitchell
authors.initials: M
authors.lastname: Knutson
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D000107:Acetylation; D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D015870:Gene Expression; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D056565:Sirtuin 2 / Q000502:physiology*; D015533:Transcriptional Activation; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000098742:Ferroportin; D007501:Iron; C474199:SIRT2 protein, human; D056565:Sirtuin 2