Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth

被引：69

作者：

Chen, Yuhan ^{[1
,2
,3
]}

Huang, Qingyang ^{[1
,2
]}

Liu, Wen ^{[1
,2
]}

Zhu, Qiong ^{[1
,2
]}

Cui, Chun-Ping ^{[1
,2
]}

Xu, Liang ^{[2
,4
]}

Guo, Xing ^{[2
,5
]}

Wang, Ping ^{[6
]}

Liu, Jingwen ^{[7
]}

Dong, Guanglong ^{[7
]}

Wei, Wenyi ^{[8
]}

Liu, Cui Hua ^{[9
]}

Feng, Zhichun ^{[3
]}

He, Fuchu ^{[1
,2
]}

Zhang, Lingqiang ^{[1
,2
,10
]}

机构：

[1] Beijing Inst Life, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Prote, Beijing 100850, Peoples R China

[2] Beijing Inst Radiat Med, Dept Genom & Prote, Beijing 100850, Peoples R China

[3] PLA Army Gen Hosp, Affiliated BaYi Childrens Hosp, Natl Engn Lab Birth Defects Prevent & Control Key, Beijing Key Lab Pediat Organ Failure, Beijing 100700, Peoples R China

[4] Anhui Med Univ, Dept Biochem & Mol Biol, Hefei 230032, Anhui, Peoples R China

[5] Nanjing Med Univ, Dept Neurobiol, Key Lab Human Funct Genom Jiangsu Prov, Nanjing 211166, Jiangsu, Peoples R China

[6] Tongji Univ, Sch Life Sci & Technol, Shanghai Peoples Hosp 10, Dept Cent Lab, Shanghai 200072, Peoples R China

[7] Chinese Peoples Liberat Army Gen Hosp, Dept Gen Surg, Beijing 100853, Peoples R China

[8] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA

[9] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China

[10] Jiangsu Normal Univ, Sch Life Sci, Xuzhou 221116, Jiangsu, Peoples R China

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

国家重点研发计划; 北京市自然科学基金;

关键词：

METABOLIC ENZYMES; OSTEOBLAST DIFFERENTIATION; PROTEIN; TARGETS; DEGRADATION; HOMEOSTASIS; EXCITATION; MUTATIONS; REGULATOR; STABILITY;

D O I：

10.1038/s41467-018-04815-3

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 of CCAR1 to 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 increased CCAR1S expression and tumor progression. Thus, SRSF5 responds to high glucose to promote cancer development, and SRSF5-CCAR1 axis may be valuable targets for cancer therapeutics.

引用

页数：21

共 62 条

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