A Conserved Splicing Silencer Dynamically Regulates O-GlcNAc Transferase Intron Retention and O-GlcNAc Homeostasis.
A Conserved Splicing Silencer Dynamically Regulates O-GlcNAc Transferase Intron Retention and O-GlcNAc Homeostasis.
复制标题
DOI：
10.1016/j.celrep.2017.07.017
复制
发表时间：
2017-08-01
期刊：
影响因子：
8.8
通讯作者：
Conrad NK
中科院分区：
文献类型：
--
作者：
Park SK;Zhou X;Pendleton KE;Hunter OV;Kohler JJ;O'Donnell KA;Conrad NK
用O-GlcNAc修饰核细胞质蛋白调节多种细胞过程，并与人类疾病有关。O-GlcNAc转移酶（OGT）和O-GlcNAcase （OGA）添加和去除O-GlcNAc，但调节其表达的机制尚不清楚。在这里，我们证明了OGT的第四个内含子的保留受到O-GlcNAc水平的调节。我们进一步定义了一个保守的内含子剪接沉默子（ISS），这是OGT内含子保留所必需的。结肠癌细胞中ISS的缺失导致OGT的增加，但O-GlcNAc的稳态是通过OGA蛋白的增加来维持的。然而，在培养和软琼脂中，iss缺失的细胞对OGA抑制非常敏感。此外，用OGA抑制剂处理的小鼠，iss缺失细胞的异种移植物肿瘤的生长受到损害。因此，iss介导的OGT内含子保留调控是OGT表达和维持O-GlcNAc稳态的关键组成部分。
Modification of nucleocytoplasmic proteins with O-GlcNAc regulates a wide variety of cellular processes and has been linked to human diseases. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) add and remove O-GlcNAc, but the mechanisms regulating their expression remain unclear. Here, we demonstrate that retention of the fourth intron of OGT is regulated in response to O-GlcNAc levels. We further define a conserved intronic splicing silencer (ISS) that is necessary for OGT intron retention. Deletion of the ISS in colon cancer cells leads to increases in OGT, but O-GlcNAc homeostasis is maintained by concomitant increases in OGA protein. However, the ISS-deleted cells are hypersensitive to OGA inhibition in culture and in soft agar. Moreover, growth of xenograft tumors from ISS-deleted cells is compromised in mice treated with an OGA inhibitor. Thus, ISS-mediated regulation of OGT intron retention is a key component in OGT expression and maintaining O-GlcNAc homeostasis.
登录
查看更多内容
影响因子：
10.5
作者：
Boutz PL;Bhutkar A;Sharp PA
通讯作者：
Sharp PA
影响因子：
64.5
作者：
Bhatt DM;Pandya-Jones A;Tong AJ;Barozzi I;Lissner MM;Natoli G;Black DL;Smale ST
通讯作者：
Smale ST
DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA
影响因子：
4.8
作者：
Muthusamy, Senthilkumar;Hong, Kyung U.;Jones, Steven P.
通讯作者：
Jones, Steven P.
影响因子：
7
作者：
Braunschweig U;Barbosa-Morais NL;Pan Q;Nachman EN;Alipanahi B;Gonatopoulos-Pournatzis T;Frey B;Irimia M;Blencowe BJ
通讯作者：
Blencowe BJ