Physiological mapping and prediction reveal stress-responsive translation initiation landscapes
- 1Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602 Japan.; Research Institute of Environmental Medicine, Nagoya Univ
Abstract
Translation initiation defines the protein output of the transcriptome, but its physiological dynamics in cells and tissues remain incompletely characterized. Here we develop TISCA2, an inhibitor-free method that captures eIF5B-associated initiating ribosomes to map translation initiation sites genome-wide. By directly identifying start sites rather than inferring translation from elongating-ribosome periodicity, TISCA2 improves the detection of short and overlapping translons. Translation of a subset of TISCA2-identified translons is supported by N-terminal proteomics and HLA-I immunopeptidomics. The arsenite-induced integrated stress response broadly redistributes start-site usage, reducing upstream initiation in favor of downstream initiation. TISCA2 further reveals tissue-specific initiation landscapes in vivo, with increased detection of downstream candidate start sites in the testis. Finally, we develop IncepTIS, a sequence-based deep learning model that predicts position-resolved and condition-dependent initiation landscapes. IncepTIS-guided optimization generates de novo mRNA 5' leaders with stress-responsive initiation patterns. Together, TISCA2 and IncepTIS provide an experimental and computational framework for mapping, predicting and engineering translation initiation in mammalian cells and tissues.
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BibTeX
@misc{ichihara2026physiological,
title = {{Physiological mapping and prediction reveal stress-responsive translation initiation landscapes}},
author = {K. Ichihara and T. Shiraishi and H. Morita and C. Shiraishi and M. Hirata and N. Yamashiki and S. Setsu and K. Tsuboyama and A. Hatano and S. Tokita and E. Mishiro-Sato and A. Sakamoto and T. Ito and K. Abe and M. Seki and Y. Suzuki and M. Ajiro and A. Yoshimi and T. Kanaseki and M. Matsumoto and S. Adachi and P. V. Baranov and T. Shimamura and A. Matsumoto},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763266},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763266v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Physiological mapping and prediction reveal stress-responsive translation initiation landscapes
AU - K. Ichihara
AU - T. Shiraishi
AU - H. Morita
AU - C. Shiraishi
AU - M. Hirata
AU - N. Yamashiki
AU - S. Setsu
AU - K. Tsuboyama
AU - A. Hatano
AU - S. Tokita
AU - E. Mishiro-Sato
AU - A. Sakamoto
AU - T. Ito
AU - K. Abe
AU - M. Seki
AU - Y. Suzuki
AU - M. Ajiro
AU - A. Yoshimi
AU - T. Kanaseki
AU - M. Matsumoto
AU - S. Adachi
AU - P. V. Baranov
AU - T. Shimamura
AU - A. Matsumoto
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763266
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763266v1
AB - Translation initiation defines the protein output of the transcriptome, but its physiological dynamics in cells and tissues remain incompletely characterized. Here we develop TISCA2, an inhibitor-free method that captures eIF5B-associated initiating ribosomes to map translation initiation sites genome-wide. By directly identifying start sites rather than inferring translation from elongating-ribosome periodicity, TISCA2 improves the detection of short and overlapping translons. Translation of a subset of TISCA2-identified translons is supported by N-terminal proteomics and HLA-I immunopeptidomics. The arsenite-induced integrated stress response broadly redistributes start-site usage, reducing upstream initiation in favor of downstream initiation. TISCA2 further reveals tissue-specific initiation landscapes in vivo, with increased detection of downstream candidate start sites in the testis. Finally, we develop IncepTIS, a sequence-based deep learning model that predicts position-resolved and condition-dependent initiation landscapes. IncepTIS-guided optimization generates de novo mRNA 5' leaders with stress-responsive initiation patterns. Together, TISCA2 and IncepTIS provide an experimental and computational framework for mapping, predicting and engineering translation initiation in mammalian cells and tissues.
ER -