2. Academic Validation
  3. Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites

Sec22b regulates phagosome maturation by promoting ORP8-mediated lipid exchange at endoplasmic reticulum-phagosome contact sites

  • Commun Biol. 2023 Oct 4;6(1):1008. doi: 10.1038/s42003-023-05382-0.
Nina Criado Santos 1,  Samuel Bouvet 2,  Maria Cruz Cobo 1,  Marion Mandavit 1,  Flavien Bermont 2,  Cyril Castelbou 2,  Farah Mansour 1,  Maral Azam 1,  Francesca Giordano 3 4,  Paula Nunes-Hasler 5
Affiliations

Affiliations

  • 1 Department of Pathology and Immunology, Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva, Centre Médicale Universitaire, 1 Rue Michel-Servet, Geneva, Switzerland.
  • 2 Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Centre Médicale Universitaire, 1 Rue Michel-Servet, Geneva, Switzerland.
  • 3 Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, Gif-sur-Yvette cedex, 91198, France.
  • 4 Inserm U1280, Gif-sur-Yvette cedex, 91198, France.
  • 5 Department of Pathology and Immunology, Geneva Center for Inflammation Research, Faculty of Medicine, University of Geneva, Centre Médicale Universitaire, 1 Rue Michel-Servet, Geneva, Switzerland. [email protected].
PMID: 37794132 DOI: 10.1038/s42003-023-05382-0
Abstract

Phagosome maturation is critical for immune defense, defining whether ingested material is destroyed or converted into antigens. Sec22b regulates phagosome maturation, yet how has remained unclear. Here we show Sec22b tethers endoplasmic reticulum-phagosome membrane contact sites (MCS) independently of the known tether STIM1. Sec22b knockdown increases calcium signaling, phagolysosome fusion and antigen degradation and alters phagosomal Phospholipids PI(3)P, PS and PI(4)P. Levels of PI(4)P, a lysosome docking lipid, are rescued by Sec22b re-expression and by expression of the artificial tether MAPPER but not the MCS-disrupting mutant Sec22b-P33. Moreover, Sec22b co-precipitates with the PS/PI(4)P exchange protein ORP8. Wild-type, but not mutant ORP8 rescues phagosomal PI(4)P and reduces antigen degradation. Sec22b, MAPPER and ORP8 but not P33 or mutant-ORP8 restores phagolysosome fusion in knockdown cells. These findings clarify an alternative mechanism through which Sec22b controls phagosome maturation and beg a reassessment of the relative contribution of Sec22b-mediated fusion versus tethering to phagosome biology.

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