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GPCR/endocytosis/ERK signaling/S2R is involved in the regulation of the internalization, mitochondria-targeting and -activating properties of human salivary histatin 1
International Journal of Oral Science ( IF 10.8 ) Pub Date : 2022-08-15 , DOI: 10.1038/s41368-022-00181-5
Dandan Ma 1, 2, 3 , Wei Sun 1 , Cuicui Fu 1 , Kamran Nazmi 1 , Enno C I Veerman 1 , Richard T Jaspers 3 , Jan G M Bolscher 1 , Floris J Bikker 1 , Gang Wu 4, 5
Affiliation  

Human salivary histatin 1 (Hst1) exhibits a series of cell-activating properties, such as promoting cell spreading, migration, and metabolic activity. We recently have shown that fluorescently labeled Hst1 (F-Hst1) targets and activates mitochondria, presenting an important molecular mechanism. However, its regulating signaling pathways remain to be elucidated. We investigated the influence of specific inhibitors of G protein-coupled receptors (GPCR), endocytosis pathways, extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, p38 signaling, mitochondrial respiration and Na+/K+-ATPase activity on the uptake, mitochondria-targeting and -activating properties of F-Hst1. We performed a siRNA knockdown (KD) to assess the effect of Sigma-2 receptor (S2R) /Transmembrane Protein 97 (TMEM97)—a recently identified target protein of Hst1. We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1. Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1. The inhibitors of GPCR, ERK1/2, phagocytosis, and clathrin-mediated endocytosis (CME) as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake, which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity. Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1. We further showed the intracellular trafficking and targeting process of F-Hst1, in which early endosome plays an important role. Overall, phagocytosis, CME, GPCR, ERK signaling, and S2R/TMEM97 are involved in the internalization of Hst1, while only CME and S2R/TMEM97 are critical for its subcellular targeting. The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.



中文翻译:

GPCR/内吞作用/ERK 信号/S2R 参与调节人唾液组蛋白 1 的内化、线粒体靶向和激活特性

人类唾液组蛋白 1 (Hst1) 表现出一系列细胞激活特性,例如促进细胞扩散、迁移和代谢活动。我们最近表明,荧光标记的 Hst1 (F-Hst1) 靶向并激活线粒体,呈现出一种重要的分子机制。然而,其调节信号通路仍有待阐明。我们研究了 G 蛋白偶联受体 (GPCR)、内吞途径、细胞外信号调节激酶 1/2 (ERK1/2) 信号、p38 信号、线粒体呼吸和 Na+/K+-ATPase 活性对摄取的影响。 ,F-Hst1 的线粒体靶向和激活特性。我们进行了 siRNA 敲低 (KD) 以评估 Sigma-2 受体 (S2R) /跨膜蛋白 97 (TMEM97)(一种最近发现的 Hst1 靶蛋白)的作用。我们还采用活细胞成像来监测 F-Hst1 的整个细胞内运输过程。我们的研究结果表明,细胞呼吸的抑制阻碍了 F-Hst1 的内化。GPCR、ERK1/2、吞噬作用和网格蛋白介导的内吞作用 (CME) 抑制剂以及 S2R/TMEM97 的 siRNA KD 显着降低了摄取,伴随着 F-Hst1 对细胞代谢的促进作用失效活动。只有 S2R/TMEM97 的 CME 和 KD 抑制剂显着损害了 Hst1 的线粒体靶向。我们进一步展示了 F-Hst1 的细胞内运输和靶向过程,其中早期内体起重要作用。总体而言,吞噬作用、CME、GPCR、ERK 信号和 S2R/TMEM97 参与 Hst1 的内化,而只有 CME 和 S2R/TMEM97 对其亚细胞靶向至关重要。抑制 Hst1 的内化或线粒体靶向可能会显着损害其线粒体激活特性。

更新日期:2022-08-15
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