ZAK activation on colliding ribosomes triggers SAPK signaling pathways to regulate cell fate
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ABSTRACT:
PROVIDER: PRJNA593553 | ENA |
REPOSITORIES: ENA
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Project description:Problems arising during translation of mRNAs lead to ribosome stalling and collisions with trailing ribosomes. These collisions are known to trigger a series of events including degradation of the stalled nascent polypeptide, decay of the problematic mRNAs, and ribosome rescue. However, the systemic cellular response of ribosome collision has not been explored. Here, we uncover a novel function for ribosome collisions in signal transduction. Using multiple translation elongation inhibitors and cellular stress conditions, we show that ribosome collisions activate both the SAPK (Stress Activated Protein Kinase) and GCN2-mediated cellular stress response pathways that lead to apoptosis and the integrated stress response (ISR), respectively. We further show that the MAPKKK ZAK functions as the sentinel for ribosome collisions, and ZAK is required for activation of both SAPKs p38/JNK and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that ZAK preferentially associates with the minimal unit of colliding ribosomes, the disome, inducing ZAK phosphorylation. While ZAK associates with elongating ribosomes under non-stressed conditions, activation of ZAK is specifically trigger by colliding ribosomes. Together, these results provide new insights into how perturbation of translational homeostasis, as read-out by colliding ribosomes, regulates cell fate.
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