2020
DOI: 10.1073/pnas.2010723117
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Type I interferon remodels lysosome function and modifies intestinal epithelial defense

Abstract: Organelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogenSalmonellaled us to discover that type I IFN (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity, and proteomic profile of lysosomes. Pro… Show more

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Cited by 18 publications
(9 citation statements)
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“…In addition, a study confirmed that in SLE, a representative type-I interferonopathy, IFNα impairs autophagic degradation of mtDNA, promoting STING activation [ 28 ]. In contrast, another study uncovered that IFN-I–dependent lysosome acidification in intestinal epithelial cells was associated with elevated Salmonella enterica serovar Typhimurium virulence gene expression and exacerbated cell death by controlling pH, and protease activity of lysosomes [ 29 ]. Thus, the underlying mechanism of the interaction between the STING pathway and autophagy during sepsis remains to be elucidated.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, a study confirmed that in SLE, a representative type-I interferonopathy, IFNα impairs autophagic degradation of mtDNA, promoting STING activation [ 28 ]. In contrast, another study uncovered that IFN-I–dependent lysosome acidification in intestinal epithelial cells was associated with elevated Salmonella enterica serovar Typhimurium virulence gene expression and exacerbated cell death by controlling pH, and protease activity of lysosomes [ 29 ]. Thus, the underlying mechanism of the interaction between the STING pathway and autophagy during sepsis remains to be elucidated.…”
Section: Discussionmentioning
confidence: 99%
“…IFITM3 is a potent interferon effector with roles in phagocytic initiation and endo-lysosomal trafficking during viral infection 100,101 . Interferon response genes, including IFITM3, can drive modifications of the lipid membrane that prevent viral fusion and promote lysosomal acidification 99,102 . IFN-I signaling has also been implicated in the maturation of autophagosomes 103 .…”
Section: Discussionmentioning
confidence: 99%
“…In some other instances, LMP and cathepsin engage effectors that result in apoptosis [37, 42]. Type I IFN induced lysosomal acidification and increased proteolysis are also seen in Salmonella-infected epithelial cells, leading to rupture of Salmonella-containing vacuoles, pathogen exposure to the cytosol and epithelial cell death [44]. Thus, type I IFNs may activate lysosomal processes of several cell types and many disease contexts.…”
Section: Discussionmentioning
confidence: 99%