Oncotarget

Research Papers: Autophagy and Cell Death:

Autophagy maintains ubiquitination-proteasomal degradation of Sirt3 to limit oxidative stress in K562 leukemia cells

Yixuan Fang, Jian Wang, Li Xu, Yan Cao, Fei Xu, Lili Yan, Meilan Nie, Na Yuan, Suping Zhang, Ruijin Zhao, Hongbin Wang, Mengyin Wu, Xiaoying Zhang and Jianrong Wang _

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Oncotarget. 2016; 7:35692-35702. https://doi.org/10.18632/oncotarget.9592

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Abstract

Yixuan Fang1,*, Jian Wang1,*, Li Xu1, Yan Cao1, Fei Xu1, Lili Yan1, Meilan Nie1, Na Yuan1, Suping Zhang1, Ruijin Zhao1, Hongbin Wang1, Mengyin Wu1, Xiaoying Zhang1 and Jianrong Wang1

1 Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Soochow University School of Medicine, Suzhou, China

* These authors have contributed equally to this work

Correspondence to:

Jianrong Wang, email:

Keywords: Sirt3, Autophagy, ubiquitination-proteasome pathway, oxidative stress, erythroleukemia cells

Received: January 25, 2016 Accepted: May 13, 2016 Published: May 25, 2016

Abstract

Sirtuin protein family member 3 (Sirt3) has been suggested as a positive regulator in alleviating oxidative stress by acting on the mitochondrial antioxidant machinery in solid tumors; however, its role and regulation in hematological malignancies has been poorly understood. Here, we show that contrary to what has been reported in solid tumors, in K562 leukemia cells elevated Sirt3 was associated with mitochondrial stress, and depletion of Sirt3 decreased reactive oxygen species (ROS) generation and lipid oxidation, but increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), suggesting an opposite role of Sirt3 in regulating oxidative stress in the leukemia cells. Notably, loss of autophagy by deletion of autophagy essential gene or by pharmacological inhibition on autophagic degradation caused a significant accumulation of Sirt3. However, induced activation of autophagy did not cause autophagic degradation of Sirt3. Furthermore, inhibiting proteasome activity accumulated Sirt3 in autophagy-intact but not autophagy-defective cells, and disrupting functional autophagy either genetically or pharmacologically caused significantly less ubiquitination of Sirt3. Therefore, our data suggest that basal but not enhanced autophagy activity maintains ubiquitination-proteasomal degradation of Sirt3 to limit lipid oxidative stress, representing an adaptive mechanism by which autophagy, in collaboration with the ubiquitination-proteasomal system, controls oxidative stress by controlling the levels of certain proteins in K562 leukemia cells.


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