Huth, Michelle, Santini, Laura, Galimberti, Elena, Ramesmayer, Julia, Titz-Teixeira, Fabian, Sehlke, Robert, Oberhuemer, Michael ORCID: 0000-0003-2273-2782, Stummer, Sarah, Herzog, Veronika, Garmhausen, Marius, Romeike, Merrit ORCID: 0000-0002-5890-2213, Chugunova, Anastasia, Leesch, Friederike, Holcik, Laurenz ORCID: 0000-0001-7855-3770, Weipoltshammer, Klara, Lackner, Andreas, Schoefer, Christian, von Haeseler, Arndt ORCID: 0000-0002-3366-4458, Buecker, Christa, Pauli, Andrea, Ameres, Stefan L., Smith, Austin, Beyer, Andreas and Leeb, Martin (2022). NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation. Genes Dev., 36 (5-6). S. 348 - 368. COLD SPRING HARBOR: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT. ISSN 1549-5477

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Abstract

Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2(PTC)). NMD deficiency leads to translation of the truncated eIF4A2(PTC) protein. eIF4A2(PTC) elicits increased mTORC1 activity and translation rates and causes differentiation delays. This establishes a previously unknown feedback loop between NMD and translation initiation. Furthermore, our results show a clear hierarchy in the severity of target deregulation and differentiation phenotypes between NMD effector KOs (Smg5 KO > Smg6 KO > Smg7 KO), which highlights heterodimer-independent functions for SMG5 and SMG7. Together, our findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Huth, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santini, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galimberti, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramesmayer, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Titz-Teixeira, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sehlke, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oberhuemer, MichaelUNSPECIFIEDorcid.org/0000-0003-2273-2782UNSPECIFIED
Stummer, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herzog, VeronikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garmhausen, MariusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Romeike, MerritUNSPECIFIEDorcid.org/0000-0002-5890-2213UNSPECIFIED
Chugunova, AnastasiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leesch, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holcik, LaurenzUNSPECIFIEDorcid.org/0000-0001-7855-3770UNSPECIFIED
Weipoltshammer, KlaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lackner, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoefer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Haeseler, ArndtUNSPECIFIEDorcid.org/0000-0002-3366-4458UNSPECIFIED
Buecker, ChristaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauli, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ameres, Stefan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, AustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beyer, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leeb, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-688185
DOI: 10.1101/gad.347690.120
Journal or Publication Title: Genes Dev.
Volume: 36
Number: 5-6
Page Range: S. 348 - 368
Date: 2022
Publisher: COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
Place of Publication: COLD SPRING HARBOR
ISSN: 1549-5477
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MESSENGER-RNA DECAY; PLURIPOTENCY; DIFFERENTIATION; INITIATION; PROTEIN; IDENTIFICATION; TRANSCRIPTOME; MAINTENANCE; REPRESSION; COMPLEXESMultiple languages
Cell Biology; Developmental Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68818

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