Sinner Marina P, Masurat Florentin, Ewbank Jonathan J, Pujol Nathalie, Bringmann Henrik
BIOTEC, Technical University Dresden, Dresden, Germany; University of Marburg, Marburg, Germany; Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Curr Biol. 2021 Feb 8;31(3):564-577.e12. doi: 10.1016/j.cub.2020.10.076. Epub 2020 Nov 30.
Wounding and infection trigger a protective innate immune response that includes the production of antimicrobial peptides in the affected tissue as well as increased sleep. Little is known, however, how peripheral wounds or innate immunity signal to the nervous system to increase sleep. We found that, during C. elegans larval molting, an epidermal tolloid/bone morphogenic protein (BMP)-1-like protein called NAS-38 promotes sleep. NAS-38 is negatively regulated by its thrombospondin domain and acts through its astacin protease domain to activate p38 mitogen-activated protein (MAP)/PMK-1 kinase and transforming growth factor β (TGF-β)-SMAD/SMA-3-dependent innate immune pathways in the epidermis that cause STAT/STA-2 and SLC6 (solute carrier)/SNF-12-dependent expression of antimicrobial peptide (AMP) genes. We show that more than a dozen epidermal AMPs act as somnogens, signaling across tissues to promote sleep through the sleep-active RIS neuron. In the adult, epidermal injury activates innate immunity and turns up AMP production to trigger sleep, a process that requires epidermal growth factor receptor (EGFR) signaling that is known to promote sleep following cellular stress. We show for one AMP, neuropeptide-like protein (NLP)-29, that it acts through the neuropeptide receptor NPR-12 in locomotion-controlling neurons that are presynaptic to RIS and that depolarize this neuron to induce sleep. Sleep in turn increases the chance of surviving injury. Thus, we found a novel mechanism by which peripheral wounds signal to the nervous system to increase protective sleep. Such a cross-tissue somnogen-signaling function of AMPs might also boost sleep in other animals, including humans.
受伤和感染会触发一种保护性的先天免疫反应，包括在受影响的组织中产生抗菌肽以及增加睡眠。然而，关于外周伤口或先天免疫如何向神经系统发出信号以增加睡眠，我们知之甚少。我们发现，在秀丽隐杆线虫幼虫蜕皮期间，一种名为NAS-38的表皮类类 tolloid/骨形态发生蛋白（BMP）-1样蛋白会促进睡眠。NAS-38受其血小板反应蛋白结构域的负调控，并通过其阿斯他汀蛋白酶结构域发挥作用，激活表皮中p38丝裂原活化蛋白（MAP）/PMK-1激酶以及转化生长因子β（TGF-β）-SMAD/SMA-3依赖性先天免疫途径，这些途径会导致抗菌肽（AMP）基因的STAT/STA-2和溶质载体（SLC6）/SNF-12依赖性表达。我们表明，十几种表皮AMP作为促眠剂，跨组织发出信号，通过睡眠活跃的RIS神经元促进睡眠。在成虫中，表皮损伤会激活先天免疫并增加AMP的产生以触发睡眠，这一过程需要表皮生长因子受体（EGFR）信号传导，已知该信号传导在细胞应激后会促进睡眠。我们发现一种AMP，即神经肽样蛋白（NLP）-29，它通过位于RIS突触前的运动控制神经元中的神经肽受体NPR-12发挥作用，并使该神经元去极化以诱导睡眠。睡眠反过来又增加了受伤后存活的机会。因此，我们发现了一种外周伤口向神经系统发出信号以增加保护性睡眠的新机制。AMP的这种跨组织促眠信号功能也可能会促进包括人类在内的其他动物的睡眠。
