Aims: Proliferative signaling involves reversible posttranslational oxidation of proteins. However, relatively few molecular targets of these modifications have been identified. We investigate the role of protein oxidation in regulation of SAMHD1 catalysis. Results: Here we report that SAMHD1 is a major target for redox regulation of nucleotide metabolism and cell cycle control. SAMHD1 is a triphosphate hydrolase, whose function involves regulation of deoxynucleotide triphosphate pools. We demonstrate that the redox state of SAMHD1 regulates its catalytic activity. We have identified three cysteine residues that constitute an intrachain disulfide bond "redox switch" that reversibly inhibits protein tetramerization and catalysis. We show that proliferative signals lead to SAMHD1 oxidation in cells and oxidized SAMHD1 is localized outside of the nucleus. Innovation and Conclusions: SAMHD1 catalytic activity is reversibly regulated by protein oxidation. These data identify a previously unknown mechanism for regulation of nucleotide metabolism by SAMHD1. Antioxid. Redox Signal. 27, 1317-1331.
Bibliographical noteFunding Information:
We thank Dr. Jingyun Lee and the staff of the Metabo-lomics and Proteomics Shared Resource of the Wake Forest School of Medicine for their assistance in the performance and analysis of mass spectrometry experiments, and Amy Molan and Michael Carpenter for comments on the article. This work has been supported through funding from the NIH (RO1 GM108827 to T.H., RO1 CA142838 to L.W.D., R01 GM06692 to F.W.P., and R33 CA177461 to L.B.P., and T32 GM095440 support for C.H.M.), Alliance for Lupus Research to F.W.P., and the Comprehensive Cancer Center of Wake Forest University National Cancer Institute Cancer Center Support Grant P30CA012197. R.S.H. is an Investigator of the Howard Hughes Medical Institute.
- Aicardi-Goutieres syndrome
- HIV restriction
- enzyme catalysis
- protein oxidation
- redox switch