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Insight into How Human Cells Fight Bacteria—and How Bacteria Fight Back

Key findings

  • Numerous bacterial effector proteins bind or modulate phospholipids, suggesting they're important in host defense, and this study investigated which lipid kinases and phosphatases are critical to xenophagy (elimination of intracellular pathogens)
  • SAC1, a transmembrane phosphoinositide phosphatase, was identified as an essential regulator of xenophagy that controls levels of phosphatidylinositol-4-phosphate [PI(4)P] on autophagosomal membranes
  • Depletion or inactivation of SAC1 delayed fusion between Salmonella-containing autophagosomes and the lysosomal compartments where enzymes degrade Salmonella; thus, bacterial replication increased
  • Mechanistically, loss of SAC1 facilitated recruitment of SteA, a PI(4)P-binding Salmonella effector protein that exacerbated the delay in lysosomal fusion
  • This improved understanding of how innate defense responses are modulated could lead to novel therapeutics for a bacterial infection that augments xenophagy

Mammalian cells use a process called xenophagy to eliminate intracellular pathogens. In response, bacteria have evolved strategies to evade xenophagy and other host cell defense mechanisms.

Salmonella serves as a good example of bacteria that resist xenophagy. Like other pathogens, it exploits membrane trafficking to establish replication-competent niches in the host cytosol.

Now, Massachusetts General Hospital researchers have revealed how host cells and Salmonella counter-regulate lipid membrane dynamics during xenophagy to modulate an innate defense. Kai Liu, PhD, research fellow at the Center for Computational and Integrative Biology, Ramnik J. Xavier, MD, PhD, director of the Center for Computational and Integrative Biology and the Center for Immunology and Inflammatory Diseases, and colleagues published their findings in Cell Reports.


Phosphoinositides are key components of cellular membranes and are controlled by factors from both mammalian cells and intracellular pathogens. Using small interfering RNA directed against phosphoinositide kinases and phosphatases, the researchers screened for regulators of the host innate defense response to intracellular bacterial replication.

Role of SAC1

The team identified regulation of phosphatidylinositol-4-phosphate [PI(4)P] by a phosphatase, SAC1 (encoded by the SACM1L gene), as having an essential role in xenophagy. In a Salmonella model:

  • Salmonella replication was elevated in cells that had SACM1L knocked down or knocked out
  • Re-expression of wild-type SAC1 restored restriction of Salmonella replication
  • Reducing PI(4)P levels in SACM1L knockout cells restricted Salmonella replication

A central mechanism of innate immunity is that bacteria become encapsulated in autophagosomes, which fuse with lysosomal compartments where enzymes degrade the bacteria. SACM1L-deficient cells accumulated PI(4)P on Salmonella-containing autophagosomes, which resulted in delayed fusion with lysosomes and increased Salmonella survival.

Role of SteA

SteA, an effector protein secreted by Salmonella that binds PI(4)P, played a direct role in blocking the degradation of Salmonella. Following the loss of SAC1, increased levels of PI(4)P on Salmonella-containing autophagosomes facilitated SteA accumulation, and SteA, in turn, exacerbated the interference with lysosomal fusion, resulting in increased Salmonella replication.

Interpreting the Findings

SAC1 participates in the innate host defense mechanism by restricting intracellular bacterial replication—it controls PI(4)P on Salmonella-containing autophagosomes and prevents recruitment of SteA, thereby preventing lysosomal fusion. This knowledge of the balance between host defense and bacterial survival may eventually lead to treatments for bacterial infections that augment xenophagy.

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