Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth.
Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth.
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剪接因子SRSF5的相互排斥的乙酰化和泛素化控制肿瘤生长
DOI：
10.1038/s41467-018-04815-3
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发表时间：
2018-06-25
影响因子：
16.6
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Chen Y;Huang Q;Liu W;Zhu Q;Cui CP;Xu L;Guo X;Wang P;Liu J;Dong G;Wei W;Liu CH;Feng Z;He F;Zhang L
大多数肿瘤细胞比正常细胞吸收更多的葡萄糖。剪接失调是癌症的分子标志之一。然而，剪接因子在葡萄糖代谢和肿瘤发展中的作用仍然不清楚。在这里，我们表明，在葡萄糖摄入量，剪接因子SRSF 5是通过Tip 60介导的乙酰化K125，拮抗Smurf 1介导的泛素化特异性诱导。SRSF 5促进CCAR 1的选择性剪接以产生CCAR 1 S蛋白，其通过增加葡萄糖消耗和乙酰辅酶A产生来促进肿瘤生长。相反，在葡萄糖饥饿时，SRSF 5被HDAC 1脱乙酰化，并被Smurf 1在相同的赖氨酸上泛素化，导致SRSF 5的蛋白酶体降解。CCAR 1 L蛋白积累促进细胞凋亡。重要的是，SRSF 5在人类肺癌中高度乙酰化和上调，这与CCAR 1 S表达增加和肿瘤进展相关。因此，SRSF 5响应于高葡萄糖促进癌症发展，并且SRSF 5-CCAR 1轴可能是癌症治疗的有价值的靶点。
Most tumor cells take up more glucose than normal cells. Splicing dysregulation is one of the molecular hallmarks of cancer. However, the role of splicing factor in glucose metabolism and tumor development remains poorly defined. Here, we show that upon glucose intake, the splicing factor SRSF5 is specifically induced through Tip60-mediated acetylation on K125, which antagonizes Smurf1-mediated ubiquitylation. SRSF5 promotes the alternative splicing ofCCAR1to produce CCAR1S proteins, which promote tumor growth by enhancing glucose consumption and acetyl-CoA production. Conversely, upon glucose starvation, SRSF5 is deacetylated by HDAC1, and ubiquitylated by Smurf1 on the same lysine, resulting in proteasomal degradation of SRSF5. The CCAR1L proteins accumulate to promote apoptosis. Importantly, SRSF5 is hyperacetylated and upregulated in human lung cancers, which correlates with increasedCCAR1Sexpression and tumor progression. Thus, SRSF5 responds to high glucose to promote cancer development, and SRSF5–CCAR1 axis may be valuable targets for cancer therapeutics.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
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影响因子：
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影响因子：
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影响因子：
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作者：
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影响因子：
64.8
作者：
Orvedahl, Anthony;Sumpter, Rhea, Jr.;Xiao, Guanghua;Ng, Aylwin;Zou, Zhongju;Tang, Yi;Narimatsu, Masahiro;Gilpin, Christopher;Sun, Qihua;Roth, Michael;Forst, Christian V.;Wrana, Jeffrey L.;Zhang, Ying E.;Luby-Phelps, Katherine;Xavier, Ramnik J.;Xie, Yang;Levine, Beth
通讯作者：
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