Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1505-1516
Number of pages12
JournalJournal of Clinical Investigation
Volume127
Issue number4
DOIs
StatePublished - Apr 3 2017

ASJC Scopus subject areas

  • Medicine(all)

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