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Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection

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  • Yang Shi

    (Xiamen University)

  • Lin Wan

    (Xiamen University)

  • Mengmeng Jiao

    (Xiamen University)

  • Chuan-qi Zhong

    (Xiamen University)

  • Huiting Cui

    (Xiamen University)

  • Jing Yuan

    (Xiamen University
    Xiamen University)

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.

Suggested Citation

  • Yang Shi & Lin Wan & Mengmeng Jiao & Chuan-qi Zhong & Huiting Cui & Jing Yuan, 2025. "Elevated NAD+ drives Sir2A-mediated GCβ deacetylation and OES localization for Plasmodium ookinete gliding and mosquito infection," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57517-y
    DOI: 10.1038/s41467-025-57517-y
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    References listed on IDEAS

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    1. Jiepeng Guan & Peijia Wu & Xiaoli Mo & Xiaolong Zhang & Wenqi Liang & Xiaoming Zhang & Lubin Jiang & Jian Li & Huiting Cui & Jing Yuan, 2024. "An axonemal intron splicing program sustains Plasmodium male development," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Heidi A. Tissenbaum & Leonard Guarente, 2001. "Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans," Nature, Nature, vol. 410(6825), pages 227-230, March.
    3. Yuanyuan Jiang & Jun Wei & Huiting Cui & Chuanyuan Liu & Yuan Zhi & ZhengZheng Jiang & Zhenkui Li & Shaoneng Li & Zhenke Yang & Xu Wang & Pengge Qian & Cui Zhang & Chuanqi Zhong & Xin-zhuan Su & Jing , 2020. "An intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    4. Fang Wu & Natali H. Muskat & Inbar Dvilansky & Omri Koren & Anat Shahar & Roi Gazit & Natalie Elia & Eyal Arbely, 2023. "Acetylation-dependent coupling between G6PD activity and apoptotic signaling," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
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