eIF2D promotes 40S ribosomal subunit recycling during intrinsic ribosome destabilization
Although eukaryotic initiation factor 2D (eIF2D) is implicated in translation initiation, reinitiation, and ribosome recycling, its precise role remains unclear. Here, we show that eIF2D promotes 40S ribosome recycling during intrinsic ribosome destabilization (IRD), a process in which ribosomes stochastically destabilize while translating proteins with consecutive acidic amino acids at their NH2-terminus. Unrecycled 40S ribosomes accumulate in eIF2D-deficient cells, leading to 80S ribosome stalling. Selective translation complex profiling (TCP-seq) reveals that eIF2D preferentially associates with IRD-prone regions. The winged helix domain, unique to eIF2D but absent in MCTS1-DENR, enhances its binding to 40S subunits, but likely clashes with ABCE1 during stop-codon-associated recycling. Loss of eIF2D reduces the expression of IRD-inducing proteins, including splicing factors. Together, these findings define a previously unappreciated role for eIF2D in 40S recycling and clarify its mechanistic divergence from the MCTS1-DENR complex.
Authors
- Kodai Machida (ORCID: https://orcid.org/0000-0003-4973-9685)
- Chisa Shiraishi (ORCID: https://orcid.org/0000-0002-9710-488X)
- Yuki Kito (ORCID: https://orcid.org/0000-0001-5104-0932)
- Atsushi Toyoda (ORCID: https://orcid.org/0000-0002-0728-7548)
- Masaki Matsumoto (ORCID: https://orcid.org/0000-0002-6987-0288)
- Yuhei Chadani (ORCID: https://orcid.org/0000-0003-0862-6676)
- Akinobu Matsumoto (ORCID: https://orcid.org/0000-0002-4077-3935)
- Kazuya Ichihara (ORCID: https://orcid.org/0000-0002-9354-452X)
- Taichi Shiraishi (ORCID: https://orcid.org/0009-0003-4422-1374)
- Emi Mishiro‐Sato (ORCID: https://orcid.org/0000-0001-5528-4440)
- Hideki Taguchi (ORCID: https://orcid.org/0000-0002-6612-9339)
- Yuta Takahashi (ORCID: https://orcid.org/0000-0002-5214-7077)
- Hiroaki Imataka (ORCID: https://orcid.org/0000-0002-3731-0294)
- Takuhiro Ito (ORCID: https://orcid.org/0000-0003-3704-5205)
- Atsushi Hatano (ORCID: https://orcid.org/0000-0002-0386-5080)
- Takayuki Nojima (ORCID: https://orcid.org/0000-0002-7865-873X)
- Makoto Hirata (ORCID: https://orcid.org/0000-0002-9994-9958)
- Keiichi I. Nakayama (ORCID: https://orcid.org/0000-0002-7185-1529)
- Akinao Kobo (ORCID: https://orcid.org/0000-0001-5889-1879)
Institutions
- National Institute of Genetics (JP)
- Tokyo Institute of Technology (JP)
- Kyushu University (JP)
- Okayama University (JP)
- University of Hyogo (JP)
- Himeji University (JP)
- Life Science Institute (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- Nagoya Industrial Science Research Institute (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Institute of Cell Biology (UA)
- Nagoya University (JP)
- Niigata University (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1093/nar/gkaf1322
- Citations
- 1
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Institute of Genetics