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

doi:10.1172/JCI88574

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 journal › Article › peer-review

105 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 language	English (US)
Pages (from-to)	1505-1516
Number of pages	12
Journal	Journal of Clinical Investigation
Volume	127
Issue number	4
DOIs	https://doi.org/10.1172/JCI88574
State	Published - Apr 3 2017

Funding

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.

ASJC Scopus subject areas

General Medicine

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Yang, X., Park, S. H., Chang, H. C., Shapiro, J. S., Vassilopoulos, A., Sawicki, K. T., Chen, C., Shang, M., Burridge, P. W., Epting, C. L., Wilsbacher, L. D., Jenkitkasemwong, S., Knutson, M., Gius, D., & Ardehali, H. (2017). Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. Journal of Clinical Investigation, 127(4), 1505-1516. https://doi.org/10.1172/JCI88574

@article{af9b595e39944355970241676a70a39d,

title = "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.",

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

note = "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.",

year = "2017",

month = apr,

day = "3",

doi = "10.1172/JCI88574",

language = "English (US)",

volume = "127",

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journal = "Journal of Clinical Investigation",

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publisher = "The American Society for Clinical Investigation",

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Yang, X, Park, SH, Chang, HC, Shapiro, JS, Vassilopoulos, A, Sawicki, KT, Chen, C, Shang, M, Burridge, PW , Epting, CL , Wilsbacher, LD, Jenkitkasemwong, S, Knutson, M, Gius, D & Ardehali, H 2017, 'Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2', Journal of Clinical Investigation, vol. 127, no. 4, pp. 1505-1516. https://doi.org/10.1172/JCI88574

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.

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JO - Journal of Clinical Investigation

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IS - 4

ER -

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

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