Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2
Xiaoyan Yang, … , David Gius, Hossein Ardehali
Xiaoyan Yang, … , David Gius, Hossein Ardehali
Published March 13, 2017
Citation Information: J Clin Invest. 2017;127(4):1505-1516. https://doi.org/10.1172/JCI88574.
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Research Article Cell biology Metabolism

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

Xiaoyan Yang, Seong-Hoon Park, Hsiang-Chun Chang, Jason S. Shapiro, Athanassios Vassilopoulos, Konrad T. Sawicki, Chunlei Chen, Meng Shang, Paul W. Burridge, Conrad L. Epting, Lisa D. Wilsbacher, Supak Jenkitkasemwong, Mitchell Knutson, David Gius, Hossein Ardehali

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Figure 1

SIRT2 regulates cellular iron content.

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SIRT2 regulates cellular iron content. (A) Non-heme iron content in Sirt...
(A) Non-heme iron content in Sirt2+/+ and Sirt2–/– MEFs normalized to the protein concentration (n = 5 for each genotype). (B) Cellular content of 55Fe in Sirt2+/+ and Sirt2–/– MEFs after 48 hours of incubation with radioactive iron (n = 10–12 for each genotype). (C) Non-heme iron content in HepG2 cells infected with control lentivirus (lenti-control shRNA) or SIRT2 shRNA (lenti-SIRT2 shRNA) (n = 10–12 per group). (D) Cellular content of 55Fe in HepG2 cells infected with lenti-control shRNA or lenti-SIRT2 shRNA after 48 hours of incubation with radioactive iron (n = 5–6 per group). (E) Non-heme iron content in HepG2 cells treated with DMSO or the SIRT2 inhibitor AGK2 (n = 6 per group). (F) Cellular content of 55Fe in HepG2 cells treated with DMSO or the SIRT2 inhibitor AGK2 overnight after 48 hours of incubation with radioactive iron (n = 6 per group). (G) Non-heme iron content in Sirt2–/– MEFs infected with lenti-control, lenti-Sirt2-WT, or lenti-Sirt2-DN (n = 10–11 per group). Data are presented as the mean ± SEM. *P < 0.05, by Student’s t test (A–F) or 1-way ANOVA with Bonferroni’s correction for multiple comparisons (G).