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.
View: Text | PDF
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

×

Figure 6

SIRT2 regulates cellular iron homeostasis in vivo and protects against primary hepatocyte death in iron deficiency.

Options: View larger image (or click on image) Download as PowerPoint
SIRT2 regulates cellular iron homeostasis in vivo and protects against p...
(A) NRF2 acetylation levels in the livers of Sirt2+/+ and Sirt2–/– mice (n = 3 per genotype). (B) Non-heme iron content in the livers of Sirt2+/+ and Sirt2–/– mice (n = 5 per genotype). (C) Tfrc and Fpn1 mRNA levels in the livers of Sirt2+/+ and Sirt2–/– mice (n = 8 per genotype). (D) FPN1 protein levels in the livers of Sirt2+/+ and Sirt2–/– mice (n = 4 per genotype). (E) Steady-state cell numbers in primary hepatocytes from Sirt2+/+ and Sirt2–/– mice, as measured by MTS assay after treatment with DFO (n = 1 per genotype; cells cultured in 5 to 6 individual wells per genotype). (F) Cell death in primary hepatocytes from Sirt2+/+ and Sirt2–/– mice measured by PI staining (n = 1 per genotype; cells were cultured in 5 or 6 individual wells per genotype). Original magnification, ×200; scale bar: 50 μm. Data are presented as the mean ± SEM. *P < 0.05, by Student’s t test (A–D) or ANOVA with Bonferroni’s correction for multiple comparisons (E and F).