Autophagy maintains ubiquitination-proteasomal degradation of Sirt3 to limit oxidative stress in K562 leukemia cells.
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.
['Fang|Yixuan|Y|', 'Wang|Jian|J|', 'Xu|Li|L|', 'Cao|Yan|Y|', 'Xu|Fei|F|', 'Yan|Lili|L|', 'Nie|Meilan|M|', 'Yuan|Na|N|', 'Zhang|Suping|S|', 'Zhao|Ruijin|R|', 'Wang|Hongbin|H|', 'Wu|Mengyin|M|', 'Zhang|Xiaoying|X|', 'Wang|Jianrong|J|']
D017209:Apoptosis D001343:Autophagy D055785:Gene Knockdown Techniques D005978:Glutathione D006801:Humans D020014:K562 Cells D050356:Lipid Metabolism D008928:Mitochondria D010084:Oxidation-Reduction D018384:Oxidative Stress D046988:Proteasome Endopeptidase Complex D034622:RNA Interference D034741:RNA, Small Interfering D017382:Reactive Oxygen Species D056566:Sirtuin 3 D054875:Ubiquitination
Autophagy Sirt3 oxidative stress erythroleukemia cells ubiquitination-proteasome pathway