O-GlcNAcylation promotes the cytosolic localization of the m6A reader YTHDF1 and colorectal cancer tumorigenesis

Li，Jie1; Ahmad，Muhammad1; Sang，Lei2; Zhan，Yahui1; Wang，Yibo3; Yan，Yonghong4; Liu，Yue1; Mi，Weixiao1; Lu，Mei2; Dai，Yu5,6; Zhang，Rou7; Dong，Meng Qiu4; Yang，Yun Gui8,9,10; Wang，Xiaohui3,11,12; Sun，Jianwei2; Li，Jing1

2023-06-01

10.1016/j.jbc.2023.104738

Journal of Biological Chemistry   影响因子和分区

0021-9258

1083-351X

O-linked GlcNAc (O-GlcNAc) is an emerging post-translation modification that couples metabolism with cellular signal transduction by crosstalk with phosphorylation and ubiquitination to orchestrate various biological processes. The mechanisms underlying the involvement of O-GlcNAc modifications in N-methyladenosine (mA) regulation are not fully characterized. Herein, we show that O-GlcNAc modifies the mA mRNA reader YTH domain family 1 (YTHDF1) and fine-tunes its nuclear translocation by the exportin protein Crm1. First, we present evidence that YTHDF1 interacts with the sole O-GlcNAc transferase (OGT). Second, we verified Ser196/Ser197/Ser198 as the YTHDF1 O-GlcNAcylation sites, as described in numerous chemoproteomic studies. Then we constructed the O-GlcNAc-deficient YTHDF1-S196A/S197F/S198A (AFA) mutant, which significantly attenuated O-GlcNAc signals. Moreover, we revealed that YTHDF1 is a nucleocytoplasmic protein, whose nuclear export is mediated by Crm1. Furthermore, O-GlcNAcylation increases the cytosolic portion of YTHDF1 by enhancing binding with Crm1, thus upregulating downstream target (e.g. c-Myc) expression. Molecular dynamics simulations suggest that O-GlcNAcylation at S197 promotes the binding between the nuclear export signal motif and Crm1 through increasing hydrogen bonding. Mouse xenograft assays further demonstrate that YTHDF1-AFA mutants decreased the colon cancer mass and size via decreasing c-Myc expression. In sum, we found that YTHDF1 is a nucleocytoplasmic protein, whose cytosolic localization is dependent on O-GlcNAc modification. We propose that the OGT–YTHDF1–c-Myc axis underlies colorectal cancer tumorigenesis.

c-Myc Crm1 m6A O-GlcNAc YTHDF1

EI

英语

NI论文

其他

National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[31872720];National Outstanding Youth Science Fund Project of National Natural Science Foundation of China[32271285];

20232114115081

Diseases ; Molecular dynamics ; Proteins ; Signal transduction

Biology:461.9 ; Physical Chemistry:801.4 ; Organic Compounds:804.1

BIOLOGY & BIOCHEMISTRY

2-s2.0-85159579007

Scopus

1.Beijing Key Laboratory of DNA Damage Response and College of Life Sciences,Capital Normal University,Beijing,China
2.Center for Life Sciences,School of Life Sciences,State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan,Yunnan University,Kunming,China
3.Laboratory of Chemical Biology,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun,China
4.National Institute of Biological Sciences,Beijing,China
5.Department of Stomatology,Shenzhen Peoples Hospital,The Second Clinical Medical College,Jinan University,Shenzhen,China
6.The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen,Guangdong,China
7.School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,Guangdong,China
8.CAS Key Laboratory of Genomic and Precision Medicine,Collaborative Innovation Center of Genetics and Development,College of Future Technology,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing,China
9.University of Chinese Academy of Sciences,Beijing,China
10.Institute of Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing,China
11.School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei,Anhui,China
12.Beijing National Laboratory for Molecular Sciences,Beijing,China

Li，Jie,Ahmad，Muhammad,Sang，Lei,et al. O-GlcNAcylation promotes the cytosolic localization of the m6A reader YTHDF1 and colorectal cancer tumorigenesis[J]. Journal of Biological Chemistry,2023,299(6).

Li，Jie.,Ahmad，Muhammad.,Sang，Lei.,Zhan，Yahui.,Wang，Yibo.,...&Li，Jing.(2023).O-GlcNAcylation promotes the cytosolic localization of the m6A reader YTHDF1 and colorectal cancer tumorigenesis.Journal of Biological Chemistry,299(6).

Li，Jie,et al."O-GlcNAcylation promotes the cytosolic localization of the m6A reader YTHDF1 and colorectal cancer tumorigenesis".Journal of Biological Chemistry 299.6(2023).