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Plasmodium UIS3 avoids host cell-autonomous exclusion that requires GABARAPs but not LC3 and autophagy

Ariel Pradipta1, Hironori Bando2, Ji Su Ma1

  • 1Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.

Parasitology International
|March 27, 2021
PubMed

Insights

Malaria parasites use UIS3 protein to evade host defenses. This study reveals GABARAPs, not LC3, suppress UIS3-deficient parasite growth independently of autophagy.

Area of Science:

  • Cell Biology
  • Parasitology
  • Immunology

Background:

  • Malaria parasites (Plasmodium) form parasitophorous vacuoles (PVs) in liver cells.
  • The PV membrane is decorated with host LC3 and parasite UIS3, which inhibits LC3-mediated autophagy.
  • UIS3-deficient parasites replicate in autophagy-impaired cells, suggesting a role for autophagy in restricting parasite growth.

Purpose of the Study:

  • To investigate the role of autophagy proteins in restricting the growth of UIS3-deficient malaria parasites.
  • To determine if other autophagy-related proteins, beyond LC3, are involved in controlling parasite replication.

Main Methods:

  • Utilized gene-deficient cell lines lacking specific autophagy proteins (Atg9, Atg14, LC3, GABARAPs).
  • Assessed the replication of wild-type and UIS3-deficient Plasmodium sporozoites in these cell lines.
  • Analyzed the interaction between parasite UIS3 and host autophagy machinery.

Main Results:

  • Atg9 and Atg14 are dispensable for restricting UIS3-deficient parasite growth.
  • Cells lacking LC3 also restrict UIS3-deficient parasite growth, challenging the initial model.
  • GABARAPs, a distinct subfamily of Atg8 proteins, actively suppress UIS3-deficient parasite growth.

Conclusions:

  • The restriction of UIS3-deficient malaria parasites is independent of canonical LC3-mediated autophagy.
  • GABARAPs play a crucial role in suppressing parasite growth, suggesting a novel host defense mechanism.
  • UIS3's evasion strategy may involve manipulating GABARAP-dependent pathways rather than solely LC3-autophagy.
Keywords:
Atg proteinsAutophagyGABARAPsLC3sPlasmodium bergheiUpregulated in infective sporozoites 3 (UIS3)

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