Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection
Abstract cGMP signal-activated ookinete gliding is essential for mosquito midgut infection of Plasmodium in malaria transmission. During ookinete development, cGMP synthesizer GCβ polarizes to a unique localization “ookinete extrados site” (OES) until ookinete maturation and activates cGMP signaling...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57517-y |
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| author | Yang Shi Lin Wan Mengmeng Jiao Chuan-qi Zhong Huiting Cui Jing Yuan |
| author_facet | Yang Shi Lin Wan Mengmeng Jiao Chuan-qi Zhong Huiting Cui Jing Yuan |
| author_sort | Yang Shi |
| collection | DOAJ |
| description | Abstract cGMP signal-activated ookinete gliding is essential for mosquito midgut infection of Plasmodium in malaria transmission. During ookinete development, cGMP synthesizer GCβ polarizes to a unique localization “ookinete extrados site” (OES) until ookinete maturation and activates cGMP signaling for initiating parasite motility. However, the mechanism underlying GCβ translocation from cytosol to OES remains elusive. Here, we use protein proximity labeling to search the GCβ-interacting proteins in ookinetes of the rodent malaria parasite P. yoelii, and find the top hit Sir2A, a NAD+-dependent sirtuin family deacetylase. Sir2A interacts with GCβ throughout ookinete development. In mature ookinetes, Sir2A co-localizes with GCβ at OES in a mutually dependent manner. Parasites lacking Sir2A lose GCβ localization at OES, ookinete gliding, and mosquito infection, phenocopying GCβ deficiency. GCβ is acetylated at gametocytes but is deacetylated by Sir2A for OES localization at mature ookinetes. We further demonstrate that the level of NAD+, an essential co-substrate for sirtuin, increases during the ookinete development. NAD+ at its maximal level in mature ookinetes promotes Sir2A-catalyzed GCβ deacetylation, ensuring GCβ localization at OES. This study highlights the spatiotemporal coordination of cytosolic NAD+ level and NAD+-dependent Sir2A in regulating GCβ deacetylation and dynamic localization for Plasmodium ookinete gliding. |
| format | Article |
| id | doaj-art-7f35c150d0ab4823a61334702a85c8f3 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-7f35c150d0ab4823a61334702a85c8f32025-08-20T03:05:55ZengNature PortfolioNature Communications2041-17232025-03-0116111810.1038/s41467-025-57517-yElevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infectionYang Shi0Lin Wan1Mengmeng Jiao2Chuan-qi Zhong3Huiting Cui4Jing Yuan5State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityState Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen UniversityAbstract cGMP signal-activated ookinete gliding is essential for mosquito midgut infection of Plasmodium in malaria transmission. During ookinete development, cGMP synthesizer GCβ polarizes to a unique localization “ookinete extrados site” (OES) until ookinete maturation and activates cGMP signaling for initiating parasite motility. However, the mechanism underlying GCβ translocation from cytosol to OES remains elusive. Here, we use protein proximity labeling to search the GCβ-interacting proteins in ookinetes of the rodent malaria parasite P. yoelii, and find the top hit Sir2A, a NAD+-dependent sirtuin family deacetylase. Sir2A interacts with GCβ throughout ookinete development. In mature ookinetes, Sir2A co-localizes with GCβ at OES in a mutually dependent manner. Parasites lacking Sir2A lose GCβ localization at OES, ookinete gliding, and mosquito infection, phenocopying GCβ deficiency. GCβ is acetylated at gametocytes but is deacetylated by Sir2A for OES localization at mature ookinetes. We further demonstrate that the level of NAD+, an essential co-substrate for sirtuin, increases during the ookinete development. NAD+ at its maximal level in mature ookinetes promotes Sir2A-catalyzed GCβ deacetylation, ensuring GCβ localization at OES. This study highlights the spatiotemporal coordination of cytosolic NAD+ level and NAD+-dependent Sir2A in regulating GCβ deacetylation and dynamic localization for Plasmodium ookinete gliding.https://doi.org/10.1038/s41467-025-57517-y |
| spellingShingle | Yang Shi Lin Wan Mengmeng Jiao Chuan-qi Zhong Huiting Cui Jing Yuan Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection Nature Communications |
| title | Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection |
| title_full | Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection |
| title_fullStr | Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection |
| title_full_unstemmed | Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection |
| title_short | Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection |
| title_sort | elevated nad drives sir2a mediated gcβ deacetylation and oes localization for plasmodium ookinete gliding and mosquito infection |
| url | https://doi.org/10.1038/s41467-025-57517-y |
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