2. Academic Validation
  3. Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice

Palmitoylation of TBK1 enhances the type I interferon signaling and strengthens anti-malarial immunity in mice

  • Nat Commun. 2025 Nov 18;16(1):10109. doi: 10.1038/s41467-025-65081-8.
Zhongxin Han # 1,  Siyi Xiong # 1,  Ke Zeng # 1,  Zilong Xiao # 1,  Liying Zhang 1,  Yufen Zhang 1,  Jiaying Guo 1,  Wenqiang Peng 1,  Yingchao Xie 1,  Weiwei Liu 1,  Xiao Yu 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 3 Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 4 Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 5 State Key Laboratory of Multi-organ Injury Prevention and Treatment, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41253837 DOI: 10.1038/s41467-025-65081-8
Abstract

Precise regulation of type I interferon signaling is crucial for effective immune defense against infectious diseases. However, the molecular mechanisms governing this pathway are not fully understood. Here, we show a function for palmitoylation in enhancing anti-malarial immune responses. Our findings reveal that ZDHHC9 enhances the type I interferon signaling by palmitoylating TBK1 at cysteine 292. Following Infection with Plasmodium yoelii N67, the delicate balance between palmitoylation and depalmitoylation of TBK1 is disrupted. Specifically, upregulation of APT2 promotes persistent depalmitoylation of TBK1 and triggers its selective autophagic degradation via K48-linked polyubiquitination at lysine 251/372 by E3 Ligase TRIM27. This process acts as a recognition signal for the cargo receptor NDP52, resulting in inhibition of the type I interferon pathway. Notably, inhibition of APT2 using ML349 elevates type I interferon levels and improves survival rates against N67 Infection. Here, we show that targeting APT2-mediated TBK1 depalmitoylation is a potential therapeutic strategy for malaria and may also be applicable to Other Diseases driven by dysregulated type I interferon signaling.

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Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100737
    99.47%, APT2/LYPLA2 Inhibitor