Carbon dioxide not only plays a central role in the carbon cycle, but also acts as a crucial signal in living cells. Adaptation to changing CO concentrations is critical for all organisms. Conversion of CO to HCO by carbonic anhydrase and subsequent HCO-triggered signalling are thought to be important for cellular responses to CO (refs. ). However, carbonic anhydrases are suggested to transduce a change in CO rather than be a direct CO sensor, the mechanism(s) by which organisms sense CO remain unknown. Here we demonstrate that a unique group of PP2C phosphatases from fungi and plants senses CO, but not HCO, to control diverse cellular programmes. Different from other phosphatases, these PP2Cs all have an intrinsically disordered region (IDR). They formed reversible liquid-like droplets through phase separation both in cells and in vitro, and were activated in response to elevated environmental CO in an IDR-dependent manner. The IDRs in PP2Cs are characterized by a sequence of polar amino acids enriched in serine/threonine, which provides CO responsiveness. CO-responsive activation of PP2Cs via the serine/threonine-rich IDR-mediated phase separation represents a direct CO sensing mechanism and is widely exploited.
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