ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage
Although exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.815936/full |
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| author | Hong Zheng Hong Zheng Hong Zheng Xiao Lu Xiao Lu Kai Li Feng Zhu Chenhao Zhao Taiping Liu Yan Ding Yong Fu Kun Zhang Taoli Zhou Jigang Dai Yuzhang Wu Wenyue Xu Wenyue Xu |
| author_facet | Hong Zheng Hong Zheng Hong Zheng Xiao Lu Xiao Lu Kai Li Feng Zhu Chenhao Zhao Taiping Liu Yan Ding Yong Fu Kun Zhang Taoli Zhou Jigang Dai Yuzhang Wu Wenyue Xu Wenyue Xu |
| author_sort | Hong Zheng |
| collection | DOAJ |
| description | Although exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly mediated the resistance to the killing of EEFs by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection. |
| first_indexed | 2024-12-19T19:08:56Z |
| format | Article |
| id | doaj.art-b99a6ea8ff6c408bba31e774ab94e2a3 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T19:08:56Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b99a6ea8ff6c408bba31e774ab94e2a32022-12-21T20:09:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-02-011310.3389/fimmu.2022.815936815936ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver StageHong Zheng0Hong Zheng1Hong Zheng2Xiao Lu3Xiao Lu4Kai Li5Feng Zhu6Chenhao Zhao7Taiping Liu8Yan Ding9Yong Fu10Kun Zhang11Taoli Zhou12Jigang Dai13Yuzhang Wu14Wenyue Xu15Wenyue Xu16Department of Pathogenic Biology, Army Medical University, Chongqing, ChinaThe Institute of Immunology, Army Medical University, Chongqing, ChinaDepartment of Thoracic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Thoracic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaDepartment of Thoracic Surgery, Xinqiao Hospital, Army Medical University, Chongqing, ChinaThe Institute of Immunology, Army Medical University, Chongqing, ChinaDepartment of Pathogenic Biology, Army Medical University, Chongqing, ChinaKey Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, ChinaAlthough exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly mediated the resistance to the killing of EEFs by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes via its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.https://www.frontiersin.org/articles/10.3389/fimmu.2022.815936/fullPlasmodiummalariasporozoitesexo-erythrocytic formscircumsporozoite proteinIFN-γ |
| spellingShingle | Hong Zheng Hong Zheng Hong Zheng Xiao Lu Xiao Lu Kai Li Feng Zhu Chenhao Zhao Taiping Liu Yan Ding Yong Fu Kun Zhang Taoli Zhou Jigang Dai Yuzhang Wu Wenyue Xu Wenyue Xu ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage Frontiers in Immunology Plasmodium malaria sporozoites exo-erythrocytic forms circumsporozoite protein IFN-γ |
| title | ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage |
| title_full | ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage |
| title_fullStr | ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage |
| title_full_unstemmed | ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage |
| title_short | ATG Ubiquitination Is Required for Circumsporozoite Protein to Subvert Host Innate Immunity Against Rodent Malaria Liver Stage |
| title_sort | atg ubiquitination is required for circumsporozoite protein to subvert host innate immunity against rodent malaria liver stage |
| topic | Plasmodium malaria sporozoites exo-erythrocytic forms circumsporozoite protein IFN-γ |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.815936/full |
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