TY - JOUR
T1 - Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate
AU - Wu, Colin Chih Chien
AU - Peterson, Amy
AU - Zinshteyn, Boris
AU - Regot, Sergi
AU - Green, Rachel
PY - 2020/7/23
Y1 - 2020/7/23
N2 - Problems arising during translation of mRNAs lead to ribosome stalling and collisions that trigger a series of quality control events. However, the global cellular response to ribosome collisions has not been explored. Here, we uncover a function for ribosome collisions in signal transduction. Using translation elongation inhibitors and general cellular stress conditions, including amino acid starvation and UV irradiation, we show that ribosome collisions activate the stress-activated protein kinase (SAPK) and GCN2-mediated stress response pathways. We show that the MAPKKK ZAK functions as the sentinel for ribosome collisions and is required for immediate early activation of both SAPK (p38/JNK) and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that although ZAK generally associates with elongating ribosomes on polysomal mRNAs, it specifically auto-phosphorylates on the minimal unit of colliding ribosomes, the disome. Together, these results provide molecular insights into how perturbation of translational homeostasis regulates cell fate.
AB - Problems arising during translation of mRNAs lead to ribosome stalling and collisions that trigger a series of quality control events. However, the global cellular response to ribosome collisions has not been explored. Here, we uncover a function for ribosome collisions in signal transduction. Using translation elongation inhibitors and general cellular stress conditions, including amino acid starvation and UV irradiation, we show that ribosome collisions activate the stress-activated protein kinase (SAPK) and GCN2-mediated stress response pathways. We show that the MAPKKK ZAK functions as the sentinel for ribosome collisions and is required for immediate early activation of both SAPK (p38/JNK) and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that although ZAK generally associates with elongating ribosomes on polysomal mRNAs, it specifically auto-phosphorylates on the minimal unit of colliding ribosomes, the disome. Together, these results provide molecular insights into how perturbation of translational homeostasis regulates cell fate.
KW - SAPK
KW - UV radiation
KW - ZAK
KW - amino acid starvation
KW - integrated stress response
KW - ribosome collisions
UR - http://www.scopus.com/inward/record.url?scp=85087985912&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087985912&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.06.006
DO - 10.1016/j.cell.2020.06.006
M3 - Article
C2 - 32610081
AN - SCOPUS:85087985912
VL - 182
SP - 404-416.e14
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -