2026-01-09 東京大学
環境ストレス(アナログ入力)を「生か死か」(デジタル出力)へ変換する細胞運命決定の分子機構
<関連情報>
- https://www.ims.u-tokyo.ac.jp/imsut/jp/about/press/page_00369.html
- https://www.ims.u-tokyo.ac.jp/imsut/content/000012175.pdf
- https://www.nature.com/articles/s41467-025-67943-7
MKK4の時空間制御はスイッチのようなJNK活性化と二元的な細胞運命決定を指示する Spatiotemporal regulation of MKK4 dictates switch-like JNK activation and binary cell-fate decisions
Hisashi Moriizumi,Takanori Nakamura,Yuji Kubota,Ryosuke Hiranuma,Youngmin Cho,Toru Kawanishi,Hiroyuki Takeda,Takashi Suzuki & Mutsuhiro Takekawa
Nature Communications Published:08 January 2026
DOI:https://doi.org/10.1038/s41467-025-67943-7
Abstract
The JNK pathway converts graded (analogue) stress stimuli into a switch-like (digital) response, thereby dictating binary, all-or-none cell-fate decisions such as survival or death. However, the underlying mechanism remains unclear. Here, we report that the stress-induced modulation of MKK4 spatiotemporal dynamics serves as an analogue-to-digital converter for JNK signalling. Under steady-state conditions, MKK4 shuttles slowly between the nucleus and cytoplasm, but its shuttling rate increases markedly under stress via JNK-mediated feedback regulation. Experimental and mathematical analyses reveal that the increased shuttling rate, coupled with the predominant nuclear localisation of MKK4, cooperatively generates a switch-like JNK activation in response to graded stress stimuli. Disruption of this mechanism provokes graded JNK activity proportional to stress intensity, thereby aberrantly triggering apoptosis, pro-inflammatory cytokine production, and developmental abnormalities, even under mild stress in human cells and zebrafish embryos. Our findings reveal the fundamental molecular mechanism that maintains biological homeostasis under fluctuating environmental conditions.
