JCI xiaoyan.pdf (2.43 MB)
Download fileSirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2
journal contribution
posted on 2019-03-05, 16:47 authored by Xiaoyan Yang, Seong-Hoon Park, Hsiang-Chun Chang, Jason Shapiro, Athanassios Vassilopoulos, Konrad T. Sawicki, Chunlei Chen, Meng Shang, Paul W. Burridge, Conrad L. Epting, Lisa D. Wilsbacher, Supak Jenkitkasemwong, Mitchell D. Knutson, David Gius, Hossein ArdehaliSIRT2 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