Innate host defense mechanisms SAC bacteria by regulating phosphoinositide kinases and phosphatases.
Kimberly L CareyKai LiuRamnik J XavierPublished in: Autophagy (2021)
Human genetics and loss-of-function studies revealed a critical role for macroautophagy/autophagy in host defense. The autophagic delivery of intracellular pathogens to lysosomes is a central mechanism of innate immunity; thus, augmentation of host xenophagy represents a promising and powerful approach to combat infections. The precise mechanisms required for autophagosome biogenesis and maturation, however, remain unclear. Using a targeted genetic screen against phosphoinositide kinases and phosphatases, our recent work identified an essential role for the phosphoinositide phosphatase SACM1L/SAC1 in xenophagy. Re-expression of wild-type or catalytically-dead SACM1L in CRISPR knockout cells confirmed that SACM1L enzymatic activity is required to suppress replication of intracellular Salmonella. Time-dependent, quantitative and live confocal imaging demonstrated that SACM1L-deficient cells accumulate phosphatidylinositol-4-phosphate (PtdIns4P) on bacteria-containing autophagosomes, resulting in delayed fusion with degradative lysosomes and reduced bacterial killing. We further discovered that the secreted Salmonella effector protein SteA, which specifically binds PtdIns4P, exacerbates the SACM1L-dependent delay in autophagosomal maturation. These findings reveal a relationship in which the balance between host defense and bacterial survival depends upon autophagosomal membrane composition.
Keyphrases
- induced apoptosis
- wild type
- cell cycle arrest
- cell death
- genome wide
- endoplasmic reticulum stress
- escherichia coli
- high resolution
- immune response
- oxidative stress
- signaling pathway
- endothelial cells
- poor prognosis
- binding protein
- dendritic cells
- cell proliferation
- listeria monocytogenes
- crispr cas
- photodynamic therapy
- copy number
- mass spectrometry
- antimicrobial resistance
- raman spectroscopy