A Conserved Kinase-Based Body-Temperature Sensor Globally Controls Alternative Splicing and Gene Expression

Homeothermic organisms maintain their core body temperature in a narrow, tightly controlled range. Whether and how subtle circadian oscillations or disease-associated changes in core body temperature are sensed and integrated in gene expression programs remain elusive. Furthermore, a thermo-sensor capable of sensing the small temperature differentials leading to temperature-dependent sex determination (TSD) in poikilothermic reptiles has not been identified. Here, we show that the activity of CDC-like kinases (CLKs) is highly responsive to physiological temperature changes, which is conferred by structural rearrangements within the kinase activation segment. Lower body temperature activates CLKs resulting in strongly increased phosphorylation of SR proteins in vitro and in vivo. This globally controls temperature-dependent alternative splicing and gene expression, with wide implications in circadian, tissue-specific, and disease-associated settings. This temperature sensor is conserved across evolution and adapted to growth temperatures of diverse poikilotherms. The dynamic temperature range of reptilian CLK homologs suggests a role in TSD. [Display omitted] •CLK kinases are thermo-sensors reactive to subtle body-temperature changes•Body temperature globally controls splicing and gene expression through CLKs•CLK homologs are evolutionarily adapted to diverse body/growth temperatures•Wide functionality of CLKs: from TSD in reptiles to circadian biology in mammals Haltenhof et al. show that the activity of CLK kinases is extremely sensitive to physiological temperature changes. This cellular thermometer is based on minor structural rearrangements of the kinase activation segment, representing a new concept in enzymology. CLKs globally control alternative splicing and gene expression in a (body) temperature-dependent manner, with wide implications ranging from circadian biology to disease conditions. This thermometer is evolutionarily adapted to the growth temperature of diverse organisms with implications for reptilian temperature dependent sex determination.