mTORC1 activity regulates post-translational modifications of glycine decarboxylase to modulate glycine metabolism and tumorigenesis.
mTORC1 activity regulates post-translational modifications of glycine decarboxylase to modulate glycine metabolism and tumorigenesis.
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mTORC1 活性调节甘氨酸脱羧酶的翻译后修饰，从而调节甘氨酸代谢和肿瘤发生
DOI：
10.1038/s41467-021-24321-3
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发表时间：
2021-07-09
影响因子：
16.6
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Liu R;Zeng LW;Gong R;Yuan F;Shu HB;Li S
甘氨酸脱羧酶（GLDC）是甘氨酸裂解系统中将甘氨酸转化为一碳单元的关键酶。GLDC通常上调，并在许多人类癌症中发挥重要作用。GLDC是否以及如何受翻译后修饰调控尚不清楚。在这里，我们报告了雷帕霉素复合物1（mTORC 1）信号的机制靶点通过诱导去乙酰化酶沉默调节蛋白3（SIRT 3）的转录来抑制GLDC在赖氨酸（K）514处的乙酰化。在抑制mTORC 1后，乙酰转移酶乙酰辅酶A乙酰转移酶1（ACAT 1）催化GLDC K514乙酰化。GLDC的这种乙酰化损害其酶活性。此外，GLDC的这种乙酰化引发了泛素连接酶NF-X1在K544处的K33连接的多泛素化，导致其通过蛋白酶体途径降解。最后，我们发现GLDC K514乙酰化抑制甘氨酸催化剂，嘧啶合成和胶质瘤的发生。我们的发现揭示了GLDC的翻译后修饰在调节其酶活性、甘氨酸代谢和肿瘤发生中的关键作用，并为诸如胶质瘤的癌症治疗提供了潜在的靶点。
Glycine decarboxylase (GLDC) is a key enzyme of glycine cleavage system that converts glycine into one-carbon units. GLDC is commonly up-regulated and plays important roles in many human cancers. Whether and how GLDC is regulated by post-translational modifications is unknown. Here we report that mechanistic target of rapamycin complex 1 (mTORC1) signal inhibits GLDC acetylation at lysine (K) 514 by inducing transcription of the deacetylase sirtuin 3 (SIRT3). Upon inhibition of mTORC1, the acetyltransferase acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes GLDC K514 acetylation. This acetylation of GLDC impairs its enzymatic activity. In addition, this acetylation of GLDC primes for its K33-linked polyubiquitination at K544 by the ubiquitin ligase NF-X1, leading to its degradation by the proteasomal pathway. Finally, we find that GLDC K514 acetylation inhibits glycine catabolism, pyrimidines synthesis and glioma tumorigenesis. Our finding reveals critical roles of post-translational modifications of GLDC in regulation of its enzymatic activity, glycine metabolism and tumorigenesis, and provides potential targets for therapeutics of cancers such as glioma.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
影响因子：
4.8
作者：
Still, Amelia J.;Floyd, Brendan J.;Pagliarini, David J.
通讯作者：
Pagliarini, David J.
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
DOI：
10.1042/bj20120118
发表时间：
2012-05-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Scott I;Webster BR;Li JH;Sack MN
通讯作者：
Sack MN
影响因子：
64.5
作者：
SABATINI, DM;ERDJUMENTBROMAGE, H;SNYDER, SH
通讯作者：
SNYDER, SH