TY - JOUR
T1 - Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2
AU - Yang, Xiaoyan
AU - Park, Seong Hoon
AU - Chang, Hsiang Chun
AU - Shapiro, Jason S.
AU - Vassilopoulos, Athanassios
AU - Sawicki, Konrad T.
AU - Chen, Chunlei
AU - Shang, Meng
AU - Burridge, Paul W.
AU - Epting, Conrad L.
AU - Wilsbacher, Lisa D.
AU - Jenkitkasemwong, Supak
AU - Knutson, Mitchell
AU - Gius, David
AU - Ardehali, Hossein
N1 - Funding Information:
Acknowledgments XY is supported by American Heart Association grant 14POST20490097. MK is supported by NIH grant DK080706. HA is supported by NIH grants K02 HL107448, R01 HL127646, and 1PO1 HL108795. DG is supported by NIH grants 2R01CA152601-A1, 1R01CA152799-01A1, 1R01CA168292-01A1; the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust; the Zell Family Foundation, and the Avon Foundation for Breast Cancer Research.
PY - 2017/4/3
Y1 - 2017/4/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85018689723&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018689723&partnerID=8YFLogxK
U2 - 10.1172/JCI88574
DO - 10.1172/JCI88574
M3 - Article
C2 - 28287409
AN - SCOPUS:85018689723
SN - 0021-9738
VL - 127
SP - 1505
EP - 1516
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -