Freie Universität Berlin, Institute of Chemistry and Biochemistry, Laboratory of RNA Biochemistry, Takustrasse 6, 14195 Berlin, Germany.
Sequencing Core Facility, Max-Planck-Institute for Molecular Genetics, Ihnestraße 63-73, Berlin 14195, Germany.
Mol Cell. 2020 Apr 2;78(1):57-69.e4. doi: 10.1016/j.molcel.2020.01.028. Epub 2020 Feb 13.
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.
恒温动物将其核心体温维持在狭窄且严格控制的范围内。微妙的昼夜节律波动以及核心体温与疾病相关的变化是否以及如何被感知并整合到基因表达程序中仍然难以捉摸。此外，能够感知导致变温动物爬行动物温度依赖性性别决定（TSD）的小温差的热敏传感器尚未被鉴定。在这里，我们表明 CDC 样激酶（CLKs）的活性对生理温度变化高度敏感，这是由激酶激活片段内的结构重排赋予的。较低的体温激活 CLKs，导致 SR 蛋白在体外和体内的磷酸化程度大大增加。这全面控制了温度依赖性的可变剪接和基因表达，在昼夜节律、组织特异性和与疾病相关的环境中具有广泛的影响。这种温度传感器在进化中是保守的，并适应了各种变温动物的生长温度。爬行动物 CLK 同源物的动态温度范围表明其在 TSD 中的作用。
