Facultative protein selenation regulates redox sensitivity, adipose tissue thermogenesis, and obesity
| Autor: | Gina Z. Lu, Mark P. Jedrychowski, Vadim N. Gladyshev, Lawrence Kazak, Steven P. Gygi, John Szpyt, Ryan Garrity, Marco Mariotti, Dina Laznik-Bogoslavski, Bruce M. Spiegelman, Michael P. Murphy, Edward T. Chouchani, Joao A. Paulo, Devin K. Schweppe |
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| Přispěvatelé: | Kazak, Lawrence [0000-0002-7591-2544], Apollo - University of Cambridge Repository |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine selenocysteine chemistry.chemical_element Adipose tissue Biochemistry Mass Spectrometry Mice Selenium 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Adipocyte Brown adipose tissue medicine Animals Cysteine Obesity Cells Cultured Uncoupling Protein 1 Facultative Multidisciplinary Selenocysteine ROS brown adipose tissue Thermogenesis Biological Sciences Thermogenin Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Adipose Tissue chemistry Reactive Oxygen Species 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2001387117 |
| Popis: | Significance Oxidation of cysteines by reactive oxygen species (ROS) initiates thermogenesis in brown and beige adipose tissues. Cellular selenols, where selenium replaces sulfur, exhibit enhanced reactivity with ROS. Here we developed a mass spectrometric method to interrogate incorporation of selenols into proteins. Unexpectedly, this approach revealed facultative incorporation of selenium into proteins that lack canonical encoding for selenocysteine. Selenium was selectively incorporated into regulatory sites on key metabolic proteins, including as selenocysteine replacing cysteine at position 253 in UCP1 uncoupling protein 1 (UCP1). Remarkably, dietary selenium supplementation elevated facultative incorporation into UCP1, elevated energy expenditure through thermogenic adipose tissue, and protected against obesity. Together, these findings reveal the existence of facultative protein selenation, which correlates with effects on thermogenic adipocyte function. Oxidation of cysteine thiols by physiological reactive oxygen species (ROS) initiates thermogenesis in brown and beige adipose tissues. Cellular selenocysteines, where sulfur is replaced with selenium, exhibit enhanced reactivity with ROS. Despite their critical roles in physiology, methods for broad and direct detection of proteogenic selenocysteines are limited. Here we developed a mass spectrometric method to interrogate incorporation of selenium into proteins. Unexpectedly, this approach revealed facultative incorporation of selenium as selenocysteine or selenomethionine into proteins that lack canonical encoding for selenocysteine. Selenium was selectively incorporated into regulatory sites on key metabolic proteins, including as selenocysteine-replacing cysteine at position 253 in uncoupling protein 1 (UCP1). This facultative utilization of selenium was initiated by increasing cellular levels of organic, but not inorganic, forms of selenium. Remarkably, dietary selenium supplementation elevated facultative incorporation into UCP1, elevated energy expenditure through thermogenic adipose tissue, and protected against obesity. Together, these findings reveal the existence of facultative protein selenation, which correlates with impacts on thermogenic adipocyte function and presumably other biological processes as well. |
| Databáze: | OpenAIRE |
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