The MTR4/hnRNPK complex surveils aberrant polyadenylated RNAs with multiple exons

• Published in: Nature communications Vol. 15; no. 1; pp. 8684 - 13
• Main Authors: Taniue, Kenzui, Sugawara, Anzu, Zeng, Chao, Han, Han, Gao, Xinyue, Shimoura, Yuki, Ozeki, Atsuko Nakanishi, Onoguchi-Mizutani, Rena, Seki, Masahide, Suzuki, Yutaka, Hamada, Michiaki, Akimitsu, Nobuyoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/63; 38/1; 38/109; 38/44; 38/70; 38/88; 38/89; 38/91; 45/90; 631/114/2410; 631/337/1645/1769; 631/337/1645/2020; 631/80/470/2284; 82/80; Condensates; DNA helicase; Exons; Exons - genetics; Exosome Multienzyme Ribonuclease Complex - genetics; Exosome Multienzyme Ribonuclease Complex - metabolism; Gene sequencing; HEK293 Cells; HeLa Cells; Heterogeneous-Nuclear Ribonucleoprotein K - genetics; Heterogeneous-Nuclear Ribonucleoprotein K - metabolism; Humanities and Social Sciences; Humans; Introns; Introns - genetics; multidisciplinary; Nucleocytoplasmic Transport Proteins - genetics; Nucleocytoplasmic Transport Proteins - metabolism; Polyadenylation; Proteins; RNA helicase; RNA Nucleotidyltransferases; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Surveillance; Surveillance systems; Transcription termination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51981-8

RNA surveillance systems degrade aberrant RNAs that result from defective transcriptional termination, splicing, and polyadenylation. Defective RNAs in the nucleus are recognized by RNA-binding proteins and MTR4, and are degraded by the RNA exosome complex. Here, we detect aberrant RNAs in MTR4-depleted cells using long-read direct RNA sequencing and 3′ sequencing. MTR4 destabilizes intronic polyadenylated transcripts generated by transcriptional read-through over one or more exons, termed 3′ e X tended T ranscripts (3XTs). MTR4 also associates with hnRNPK, which recognizes 3XTs with multiple exons. Moreover, the aberrant protein translated from KCTD13 3XT is a target of the hnRNPK-MTR4-RNA exosome pathway and forms aberrant condensates, which we name K CTD13 3 eX tended T ranscript-derived protein (KeXT) bodies. Our results suggest that RNA surveillance in human cells inhibits the formation of condensates of a defective polyadenylated transcript-derived protein. Aberrant RNAs are recognized by the RNA helicase MTR4 and degraded by the RNA exosome complex. Here the authors show that the MTR4/hnRNPK complex destabilizes defective RNAs terminated in introns, termed 3XTs.