EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway
The larval stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), one of the most lethal helminthic infections in humans. The tumor-like growth and development of the metacestode larvae within host organs are driven by a population of somatic stem cells, the germinati...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-08-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.968872/full |
| _version_ | 1811310406990299136 |
|---|---|
| author | Chonglv Feng Chonglv Feng Zhe Cheng Zhe Cheng Zhijian Xu Zhijian Xu Ye Tian Ye Tian Huimin Tian Fan Liu Damin Luo Damin Luo Yanhai Wang Yanhai Wang |
| author_facet | Chonglv Feng Chonglv Feng Zhe Cheng Zhe Cheng Zhijian Xu Zhijian Xu Ye Tian Ye Tian Huimin Tian Fan Liu Damin Luo Damin Luo Yanhai Wang Yanhai Wang |
| author_sort | Chonglv Feng |
| collection | DOAJ |
| description | The larval stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), one of the most lethal helminthic infections in humans. The tumor-like growth and development of the metacestode larvae within host organs are driven by a population of somatic stem cells, the germinative cells, which represent the only proliferative cells in the parasite. Host-derived factors have been shown to promote germinative cell proliferation. Since cells sense the external signal mainly in G1 phase of the cell cycle, host factors are expected to exert impacts on the machinery regulating G1/S phase of the germinative cells, which still remains largely unknown in E. multilocularis. In this study, we described the characterization of two key members of the G1/S phase cell-cycle regulation, EmCyclinD and EmCDK4/6. Our data show that EmCyclinD and EmCDK4/6 display significant sequence similarity to their respective mammalian homologs, and that EmCyclinD interacts with EmCDK4/6, forming a kinase-active complex to activate its substrate Rb1. EmCyclinD was actively expressed in the germinative cells. Addition of human EGF caused an elevated expression of EmCyclinD while inhibition of the EGFR-ERK signaling pathway in the parasite reduced the expression of EmCyclinD and downstream transcriptional factors. Treatment with Palbociclib, a specific CDK4/6 inhibitor, downregulated the expression of cell cycle-related factors and impeded germinative cell proliferation and vesicle formation from protoscoleces. Our data demonstrated that the EmCyclinD-EmCDK4/6 complex participates in the cell cycle regulation of germinative cells which is mediated by host EGF via the EGFR-ERK-EmCyclinD pathway in E. multilocularis. |
| first_indexed | 2024-04-13T09:58:18Z |
| format | Article |
| id | doaj.art-2d8ca355a86544e2a6d0da48d3bd4e51 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-13T09:58:18Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-2d8ca355a86544e2a6d0da48d3bd4e512022-12-22T02:51:18ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-08-011310.3389/fmicb.2022.968872968872EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathwayChonglv Feng0Chonglv Feng1Zhe Cheng2Zhe Cheng3Zhijian Xu4Zhijian Xu5Ye Tian6Ye Tian7Huimin Tian8Fan Liu9Damin Luo10Damin Luo11Yanhai Wang12Yanhai Wang13State Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaParasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaParasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaParasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaParasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaMedical College, Xiamen University, Xiamen, Fujian, ChinaMedical College, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaParasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaState Key Laboratory of Cellular Stress Biology, Faculty of Medicine and Life Sciences, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaParasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, ChinaThe larval stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), one of the most lethal helminthic infections in humans. The tumor-like growth and development of the metacestode larvae within host organs are driven by a population of somatic stem cells, the germinative cells, which represent the only proliferative cells in the parasite. Host-derived factors have been shown to promote germinative cell proliferation. Since cells sense the external signal mainly in G1 phase of the cell cycle, host factors are expected to exert impacts on the machinery regulating G1/S phase of the germinative cells, which still remains largely unknown in E. multilocularis. In this study, we described the characterization of two key members of the G1/S phase cell-cycle regulation, EmCyclinD and EmCDK4/6. Our data show that EmCyclinD and EmCDK4/6 display significant sequence similarity to their respective mammalian homologs, and that EmCyclinD interacts with EmCDK4/6, forming a kinase-active complex to activate its substrate Rb1. EmCyclinD was actively expressed in the germinative cells. Addition of human EGF caused an elevated expression of EmCyclinD while inhibition of the EGFR-ERK signaling pathway in the parasite reduced the expression of EmCyclinD and downstream transcriptional factors. Treatment with Palbociclib, a specific CDK4/6 inhibitor, downregulated the expression of cell cycle-related factors and impeded germinative cell proliferation and vesicle formation from protoscoleces. Our data demonstrated that the EmCyclinD-EmCDK4/6 complex participates in the cell cycle regulation of germinative cells which is mediated by host EGF via the EGFR-ERK-EmCyclinD pathway in E. multilocularis.https://www.frontiersin.org/articles/10.3389/fmicb.2022.968872/fullEchinococcus multilocularisgerminative cellscyclin-dependent kinasescyclinproliferation |
| spellingShingle | Chonglv Feng Chonglv Feng Zhe Cheng Zhe Cheng Zhijian Xu Zhijian Xu Ye Tian Ye Tian Huimin Tian Fan Liu Damin Luo Damin Luo Yanhai Wang Yanhai Wang EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway Frontiers in Microbiology Echinococcus multilocularis germinative cells cyclin-dependent kinases cyclin proliferation |
| title | EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway |
| title_full | EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway |
| title_fullStr | EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway |
| title_full_unstemmed | EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway |
| title_short | EmCyclinD-EmCDK4/6 complex is involved in the host EGF-mediated proliferation of Echinococcus multilocularis germinative cells via the EGFR-ERK pathway |
| title_sort | emcyclind emcdk4 6 complex is involved in the host egf mediated proliferation of echinococcus multilocularis germinative cells via the egfr erk pathway |
| topic | Echinococcus multilocularis germinative cells cyclin-dependent kinases cyclin proliferation |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.968872/full |
| work_keys_str_mv | AT chonglvfeng emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT chonglvfeng emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT zhecheng emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT zhecheng emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT zhijianxu emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT zhijianxu emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT yetian emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT yetian emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT huimintian emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT fanliu emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT daminluo emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT daminluo emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT yanhaiwang emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway AT yanhaiwang emcyclindemcdk46complexisinvolvedinthehostegfmediatedproliferationofechinococcusmultilocularisgerminativecellsviatheegfrerkpathway |