Exogenous RNA surveillance by proton-sensing TRIM25

• 成果类型: Article
• 署名作者: Kim, Myeonghwan; Pyo, Youngjoon; Hyun, Seong-In; Jeong, Minseok; Choi, Yeon; Kim, V. Narry
• 署名单位: Institute for Basic Science - Korea (IBS); Seoul National University (SNU)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13188
• DOI: 10.1126/science.ads4539
• 发表日期: 2025-04-04
• 关键词: heparan-sulfate proteoglycan; modified messenger-rna; nucleoside modifications; enhances translation; sirna delivery; pseudouridine; expression; target; activation; STABILITY

摘要

Exogenous messenger RNAs (mRNAs) require cellular machinery for delivery and translation but also encounter inhibitory factors. To investigate their regulation, we performed genome-wide CRISPR screens with in vitro-transcribed mRNAs in lipid nanoparticles (LNPs). Heparan sulfate proteoglycans (HSPGs) and vacuolar adenosine triphosphatase (V-ATPase) were identified as mediators of LNP uptake and endosomal escape, respectively. TRIM25-an RNA binding E3 ubiquitin ligase-emerged as a key suppressor inducing turnover of both linear and circular mRNAs. The endoribonucleases N4BP1 and KHNYN, along with the antiviral protein ZAP, act redundantly in TRIM25-dependent surveillance. TRIM25 specifically targets mRNAs delivered by endosomes, and its RNA affinity increases at acidic pH, suggesting activation by protons released from ruptured endosomes. N-1-methylpseudouridine modification reduces TRIM25's RNA binding, helping RNAs evade its suppressive effect. This study comprehensively maps cellular pathways regulating LNP-mRNAs, offering insights into RNA immunity and therapeutics.