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

AM. Smirnova, V. Hronová, MP. Mohammad, A. Herrmannová, S. Gunišová, D. Petráčková, P. Halada, Š. Coufal, M. Świrski, J. Rendleman, K. Jendruchová, M. Hatzoglou, P. Beznosková, C. Vogel, LS. Valášek

. 2024 ; 43 (4) : 113976. [pub] 20240319

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc24014275

Grantová podpora
R01 DK060596 NIDDK NIH HHS - United States
R35 GM127089 NIGMS NIH HHS - United States
R37 DK060596 NIDDK NIH HHS - United States

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.

Citace poskytuje Crossref.org

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