Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response |
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| Authors: | Yung‐Lin Hsieh Hong‐Yi Kuo Che‐Chang Chang Mandar T Naik Pei‐Hsin Liao Chun‐Chen Ho Tien‐Chi Huang Jen‐Chong Jeng Pang‐Hung Hsu Ming‐Daw Tsai Tai‐Huang Huang Hsiu‐Ming Shih |
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| Affiliation: | 1. Institute of Biomedical Sciences, Academia Sinica, , Taipei, Taiwan, ROC;2. Graduate Institute of Life Sciences, National Defense Medical Center, , Taipei, Taiwan, ROC;3. Graduate Institute of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, , Taipei, Taiwan, ROC;4. Institute of Molecular Medicine, College of Medicine, National Taiwan University, , Taipei, Taiwan, ROC;5. Department of Life Science, Institute of Bioscience and Biotechnology, Center for Marine Bioenvironment and Biotechnology, National Taiwan Ocean University, , Kee‐Lung, Taiwan, ROC;6. Institute of Biological Chemistry, Academia Sinica, , Taipei, Taiwan, ROC;7. Department of Physics, National Taiwan Normal University, , Taipei, Taiwan, ROC |
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| Abstract: | While numerous small ubiquitin‐like modifier (SUMO) conjugated substrates have been identified, very little is known about the cellular signalling mechanisms that differentially regulate substrate sumoylation. Here, we show that acetylation of SUMO E2 conjugase Ubc9 selectively downregulates the sumoylation of substrates with negatively charged amino acid‐dependent sumoylation motif (NDSM) consisting of clustered acidic residues located downstream from the core ψ‐K‐X‐E/D consensus motif, such as CBP and Elk‐1, but not substrates with core ψ‐K‐X‐E/D motif alone or SUMO‐interacting motif. Ubc9 is acetylated at residue K65 and K65 acetylation attenuates Ubc9 binding to NDSM substrates, causing a reduction in NDSM substrate sumoylation. Furthermore, Ubc9 K65 acetylation can be downregulated by hypoxia via SIRT1, and is correlated with hypoxia‐elicited modulation of sumoylation and target gene expression of CBP and Elk‐1 and cell survival. Our data suggest that Ubc9 acetylation/deacetylation serves as a dynamic switch for NDSM substrate sumoylation and we report a previously undescribed SIRT1/Ubc9 regulatory axis in the modulation of protein sumoylation and the hypoxia response. |
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| Keywords: | acetylation hypoxia SIRT1 sumoylation Ubc9 |
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