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INPP5D inhibits anti-malarial immunity by promoting IRF3 degradation through selective autophagy

Hongyu Li1, Xiao Yu1

  • 1Department of Immunology, Guangdong Provincial Key Lab of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Autophagy Reports
|May 21, 2025
PubMed

Insights

Inositol polyphosphate-5-phosphatase D (INPP5D) negatively regulates type I interferon (IFN-I) signaling by promoting autophagy of interferon regulatory factor 3 (IRF3) during malaria. This INPP5D pathway offers a potential therapeutic target for malaria control.

Area of Science:

  • Immunology
  • Cellular Biology
  • Parasitology

Background:

  • Inositol polyphosphate-5-phosphatase D (INPP5D) is crucial for immune cell activation.
  • Mechanisms of anti-malarial immunity remain largely unknown.
  • INPP5D's role in regulating immune responses during malaria is under investigation.

Purpose of the Study:

  • To elucidate the role of INPP5D in anti-malarial immunity.
  • To investigate the molecular mechanisms by which INPP5D regulates immune signaling during malaria.
  • To identify potential therapeutic targets for malaria.

Main Methods:

  • Investigated INPP5D's function in regulating type I interferon (IFN-I) signaling.
  • Examined the promotion of autophagic degradation of interferon regulatory factor 3 (IRF3) by INPP5D.
  • Analyzed the interaction between INPP5D, IRF3, and the autophagy receptor CALCOCO2/NDP52.
  • Studied the regulation of INPP5D by miR-155-5p following Plasmodium yoelii infection.

Main Results:

  • INPP5D acts as a negative regulator of IFN-I signaling during malaria.
  • INPP5D enhances the association of IRF3 with CALCOCO2/NDP52, promoting IRF3 ubiquitination and autophagic degradation.
  • INPP5D is downregulated by miR-155-5p, establishing a feedback loop between IFN-I signaling and autophagy.
  • INPP5D mediates crosstalk between IFN-I response and autophagy in anti-malarial immunity.

Conclusions:

  • INPP5D plays a critical role in modulating the immune response to malaria by linking IFN-I signaling and autophagy.
  • Targeting INPP5D may represent a novel therapeutic strategy for controlling malaria infection.
Keywords:
Anti-malarial immunityINPP5DIRF3selective autophagytype I interferon

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