Dear Editor,The skin barrier can be impaired by acute skin wounds,which may lead to a series of complications.It is essential to accelerate wound healing and rapidly restore the structural integrity and functionality ...Dear Editor,The skin barrier can be impaired by acute skin wounds,which may lead to a series of complications.It is essential to accelerate wound healing and rapidly restore the structural integrity and functionality of skin.One of the promising bioactive agents is human salivary histatin 1(Hst1),a 38-amino acid histidine-rich peptide that functions to maintain the homeostasis of oral mucosa with a cellular mechanism of promoting the adhesion,spreading,migration of epithelial cells and thus re-epithelialization[1].In recent years,Hst1 has been shown to be effective against various skin-related cell types,such as fibroblasts,myo-fibroblasts,keratinocytes and endothelial cells.In our latest in-vivo study,Hst1 not only promotes angiogenesis,re-epithelialization and collagen production,but also suppresses inflammation,thereby significantly accelerating acute skin wound healing in mice[2].All these studies show that Hst1 is a potent bioactive agent for accelerating acute skin wound healing.展开更多
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 an...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 kinases1/2(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 si RNA 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.展开更多
基金funded by the National Natural Science Foundation of China(82172223)the National Key Research and Development Plan of China(2017YFC1103301)+1 种基金the Military Medical Innovation Special Projects(18CXZ029)the Key Research and Development Plan of Zhejiang Province(2021C04013).
文摘Dear Editor,The skin barrier can be impaired by acute skin wounds,which may lead to a series of complications.It is essential to accelerate wound healing and rapidly restore the structural integrity and functionality of skin.One of the promising bioactive agents is human salivary histatin 1(Hst1),a 38-amino acid histidine-rich peptide that functions to maintain the homeostasis of oral mucosa with a cellular mechanism of promoting the adhesion,spreading,migration of epithelial cells and thus re-epithelialization[1].In recent years,Hst1 has been shown to be effective against various skin-related cell types,such as fibroblasts,myo-fibroblasts,keratinocytes and endothelial cells.In our latest in-vivo study,Hst1 not only promotes angiogenesis,re-epithelialization and collagen production,but also suppresses inflammation,thereby significantly accelerating acute skin wound healing in mice[2].All these studies show that Hst1 is a potent bioactive agent for accelerating acute skin wound healing.
基金funded by Eurostars project,grant number E!12764。
文摘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 kinases1/2(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 si RNA 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.
