METTL3 protects METTL14 from STUB1‐mediated degradation to maintain m6A homeostasis. (4th January 2023)

• Record Type: Journal Article
• Authors: Zeng, Zhan‐Cheng; Pan, Qi; Sun, Yu‐Meng; Huang, Heng‐Jing; Chen, Xiao‐Tong; Chen, Tian‐Qi; He, Bo; Ye, Hua; Zhu, Shun‐Xin; Pu, Ke‐Jia; Fang, Ke; Huang, Wei; Chen, Yue‐Qin; Wang, Wen‐Tao
• Is Part Of: EMBO reports. Volume 24:Number 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-01-04
• Subjects: m6A homeostasis -- METTL14 -- METTL3 -- STUB1 -- ubiquitination‐mediated degradation; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202255762
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: N 6 ‐Methyladenosine (m 6 A) is an important RNA modification catalyzed by methyltransferase‐like 3 (METTL3) and METTL14. m 6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m 6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m 6 A levels. The amino acid regions 450–454 and 464–480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m 6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine‐tune m 6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer. Synopsis: The competitive interaction of METTL3 with STUB1 controls METTL14 levels, thereby fine‐tuning m6A homeostasis. Enforced STUB1 expression delays the progression of cholangiocarcinoma by reducing METTL14 and m6A levels in the tumor. STUB1 mediates METTL14 ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation. METTL3 functions as "bodyguard" to promote METTL14 stabilization. METTL14 levels are regulated by the competitive interaction of METTL3 with STUB1 to regulate m6A homeostasis. Increasing STUB1 levels suppress tumorigenesis by targeting METTL14‐dependent RNA m6A modifications. Abstract : The competitive interaction of METTL3 with STUB1 controls METTL14 levels, thereby fine‐tuning m6A homeostasis. Enforced STUB1 expression delays the progression of cholangiocarcinoma by reducing METTL14 and m6A levels in the tumor.