Inactivation of EWS reduces PGC-1 alpha protein stability and mitochondrial homeostasis

Park Jun Hong; Kang Hong-Jun; Lee Yun KyungKang HyeogKim JihyunChung Jay H.Chang Ji SukMcPherron Alexandra C.Lee Sean Bong

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Inactivation of EWS reduces PGC-1 alpha protein stability and mitochondrial homeostasis

机译：Inactivation of EWS reduces PGC-1 alpha protein stability and mitochondrial homeostasis

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EWS (Ewing sarcoma) encodes an RNA/ssDNA binding protein that is frequently rearranged in a number of different cancers by chromosomal translocations. Physiologically, EWS has diverse and essential roles in various organ development and cellular processes. In this study, we uncovered a new role of EWS in mitochondrial homeostasis and energy metabolism. Loss of EWS leads to a significant decrease in mitochondria abundance and activity, which is caused by a rapid degradation of Peroxisome proliferator-activated receptor. Coactivator (PGC-1 alpha), a central regulator of mitochondria biogenesis, function, and cellular energy metabolism. EWS inactivation leads to increased ubiquitination and proteolysis of PGC-1 alpha via proteasome pathway. Complementation of EWS in Ews-deficient cells restores PGC-1 alpha and mitochondrial abundance. We found that expression of E3 ubiquitin ligase, FBXW7 (F-box/WD40 domain protein 7), is increased in the absence of Ews and depletion of Fbxw7 in Ews-null cells restores PGC-1 alpha expression and mitochondrial density. Consistent with these findings, mitochondrial abundance and activity are significantly reduced in brown fat and skeletal muscles of Ews-deficient mice. Furthermore, expression of mitochondrial biogenesis, respiration and fatty acid beta-oxidation genes is significantly reduced in the liver of Ews-null mice. These results demonstrate a novel role of EWS in mitochondrial and cellular energy homeostasis by controlling PGC-1 alpha protein stability, and further implicate altered mitochondrial and energy metabolism in cancers harboring the EWS translocation.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第19期|6074-6079|共6页
作者
Park Jun Hong; Kang Hong-Jun; Lee Yun KyungKang HyeogKim JihyunChung Jay H.Chang Ji SukMcPherron Alexandra C.Lee Sean Bong;
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作者单位

Tulane Univ, Sch Med, Dept Pathol & Lab Med, New Orleans, LA 70112 USA;

NIDDK, Mol Endocrinol Branch, NIH, Bethesda, MD 20892 USA;

NHLBI, Lab Obes & Aging Res, NIH, Bethesda, MD 20892 USAPennington Biomed Res Ctr, Lab Gene Regulat & Metab, Baton Rouge, LA 70808 USANIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
EWS; PGC-1alpha; protein stability; mitochondria homeostasis; energy metabolism;

Inactivation of EWS reduces PGC-1 alpha protein stability and mitochondrial homeostasis

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