Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control.

0584639 - MBÚ 2025 RIV US eng J - Journal Article
Smirnova, Anna - Hronová, Vladislava - Mohammad, Mahabub Pasha - Herrmannová, Anna - Gunišová, Stanislava - Petráčková, Denisa - Halada, Petr - Coufal, Štěpán - Swirski, M. - Rendleman, J. - Jendruchová, Kristýna - Hatzoglou, M. - Beznosková, Petra - Vogel, C. - Valášek, Leoš Shivaya
Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control.
Cell Reports. Roč. 43, č. 4 (2024), s. 113976. ISSN 2211-1247. E-ISSN 2211-1247
R&D Projects: GA ČR(CZ) GX19-25821X; GA MŠMT(CZ) EH22_008/0004575
Research Infrastructure: CIISB III - 90242
Institutional support: RVO:61388971
Keywords : ribosome * factor 4 (ATF4) * stress respon * ORF2/ATF4 overlap
OECD category: Cell biology
Impact factor: 8.8, year: 2022
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S2211124724003048?via%3Dihub

Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response, leading cells toward adaptation or death. ATF4's induction under stress was thought to be due to delayed translation reinitiation, where the reinitiation-permissive upstream open reading frame 1 (uORF1) plays a key role. Accumulating evidence challenging this mechanism as the sole source of ATF4 translation control prompted us to investigate additional regulatory routes. We identified a highly conserved stem-loop in the uORF2/ATF4 overlap, immediately preceded by a near-cognate CUG, which introduces another layer of regulation in the form of ribosome queuing. These elements explain how the inhibitory uORF2 can be translated under stress, confirming prior observations but contradicting the original regulatory model. We also identified two highly conserved, potentially modified adenines performing antagonistic roles. Finally, we demonstrated that the canonical ATF4 translation start site is substantially leaky scanned. Thus, ATF4's translational control is more complex than originally described, underpinning its key role in diverse biological processes.
Permanent Link: https://hdl.handle.net/11104/0352526


Research data: Mendeley data