Hypoxic Stress Induces LARP1-Driven Stress Granules That Protect mRNAs from Decay to Sustain Mitotic Cell Cycle Progression
Hypoxia is a defining feature of solid tumours that elicits extensive transcriptional and post-transcriptional adaptations. Stress granules (SGs) are frequently observed under hypoxia, yet how they assemble and whether they contribute to hypoxic gene regulation remain poorly understood. Here, we show that hypoxia induces SGs through an assembly mechanism distinct from that of classical acute stresses. Hypoxia SG formation occurs independently of the integrated stress response and instead requires the HIF1-REDD1-mTORCC1-4EBP1 axis. Remarkably, hypoxia SGs assemble despite robust ongoing translation, suggesting that additional mechanisms lower the threshold for RNA condensation. We identify LARP1 as a potential determinant of this process, where it promotes G3BP-dependent SG assembly specifically during hypoxia. Despite their distinct assembly mechanism, hypoxia and arsenite SGs recruit broadly similar RNA populations, with selective differences validated by single-molecule FISH, suggesting that conserved principles govern RNA partitioning across different SG states. Functionally, sequestration into hypoxia SGs correlates with enhance protein expression whereby a subset of mRNAs are protected from decay. Transcriptomic analyses further reveal that this protection sustains a broader gene-expression program enriched for MCM complex and mitotic cell-cycle regulators. Accordingly, disruption of hypoxia SGs reduces mitotic progression and proliferative competence during prolonged hypoxia. Together, our findings establish LARP1-mediated condensation as a mechanism that enables SG assembly despite ongoing translation and reveal that SG sequestration preserves selected mRNAs from decay to sustain the gene-expression programs required for long-term adaptation to hypoxia.