Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response
Ubc9 acetylation modulates distinct SUMO target modification and hypoxia response
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DOI：
10.1038/emboj.2013.5
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发表时间：
2013-03-20
期刊：
影响因子：
11.4
通讯作者：
Shih, Hsiu-Ming
中科院分区：
文献类型：
--
作者：
Hsieh, Yung-Lin;Kuo, Hong-Yi;Shih, Hsiu-Ming
虽然许多小的泛素样修饰物（SUMO）共轭底物已被确定，很少有人知道的差异调节底物SUMO化的细胞信号转导机制。在这里，我们发现SUMO E2缀合酶Ubc 9的乙酰化选择性地下调具有带负电荷的氨基酸依赖性SUMO化基序（NDSM）的底物的SUMO化，所述NDSM由位于核心psi-K-X-E/D共有基序下游的成簇酸性残基组成，例如CBP和Elk-1，但不下调具有单独的核心psi-K-X-E/D基序或SUMO相互作用基序的底物的SUMO化。Ubc 9在残基K65处被乙酰化，并且K65乙酰化减弱了Ubc 9与NDSM底物的结合，导致NDSM底物类小泛素化的减少。此外，Ubc 9 K65乙酰化可通过SIRT 1被缺氧下调，并且与缺氧引起的sumo化和CBP和Elk-1的靶基因表达以及细胞存活的调节相关。我们的数据表明，Ubc 9乙酰化/脱乙酰化作为一个动态开关NDSM底物类小泛素化，我们报告了一个以前未描述的SIRT 1/Ubc 9调节轴蛋白类小泛素化和缺氧反应的调制。The EMBO Journal（2013）32，791-804. doi：10.1038/daj.2013.5; 2013年2月8日在线发布
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 psi-K-X-E/D consensus motif, such as CBP and Elk-1, but not substrates with core psi-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. The EMBO Journal (2013) 32, 791-804. doi:10.1038/emboj.2013.5; Published online 8 February 2013