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Review
. 2021 Dec;116(6):1420-1432.
doi: 10.1111/mmi.14841. Epub 2021 Nov 22.

Cytosolic detection of phagosomal bacteria-Mechanisms underlying PAMP exodus from the phagosome into the cytosol

Stephanie A Ragland  1 , Jonathan C Kagan  1
Affiliations
Review

Cytosolic detection of phagosomal bacteria-Mechanisms underlying PAMP exodus from the phagosome into the cytosol

Stephanie A Ragland et al. Mol Microbiol. 2021 Dec.

Abstract

The metazoan innate immune system senses bacterial infections by detecting highly conserved bacterial molecules, termed pathogen-associated molecular patterns (PAMPs). PAMPs are detected by a variety of host pattern recognition receptors (PRRs), whose function is to coordinate downstream immune responses. PRR activities are, in part, regulated by their subcellular localizations. Accordingly, professional phagocytes can detect extracellular bacteria and their PAMPs via plasma membrane-oriented PRRs. Conversely, phagocytosed bacteria and their PAMPs are detected by transmembrane PRRs oriented toward the phagosomal lumen. Even though PAMPs are unable to passively diffuse across membranes, phagocytosed bacteria are also detected by PRRs localized within the host cell cytosol. This phenomenon is explained by phagocytosis of bacteria that specialize in phagosomal escape and cytosolic residence. Contrary to this cytosolic lifestyle, most bacteria studied to date spend their entire intracellular lifestyle contained within phagosomes, yet they also stimulate cytosolic PRRs. Herein, we will review our current understanding of how phagosomal PAMPs become accessible to cytosolic PRRs, as well as highlight knowledge gaps that should inspire future investigations.

Keywords: STING; cGAS; caspase-11; caspase-4; caspase-5; cyclic dinucleotides; guanylate binding proteins; lipopolysaccharide; macrophage; pathogen-associated molecular pattern; pattern recognition receptor; phagosome.

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Figures

Figure 1.
Figure 1.. cGAS-STING pathway activation by cytosolic bacteria.
Bacteria that escape the phagosome and reside within the cytosol can release cyclic dinucleotides (CDNs) that directly bind to the endoplasmic reticulum (ER)-resident, transmembrane protein STING. Alternatively, bacterial lysis within the cytosol can release DNA that is detected by cGAS. DNA binding to cGAS results in the enzymatic production of the host CDN, termed cGAMP, that also binds to STING. Binding of either bacterial- or host-derived CDNs to STING on the ER facilitates translocation of STING to the Golgi. There, STING can interact with TBK1, ultimately allowing for TBK1-mediated phosphorylation of IRF3, a transcription factor that promotes type I interferon transcription. STING activation by CDNs can result in other cellular events, including induction of autophagy and activation of NF-κB, a proinflammatory cytokine transcription factor.
Figure 2.
Figure 2.. Caspase-11 activation by cytosolic LPS-containing, Gram-negative bacteria.
Gram-negative bacteria in the cytosol can be targeted by guanylate binding proteins (GBPs). There, GBP-bacteria interactions result in extraction of lipopolysaccharide (LPS), as well as recruitment of murine caspase-11 and its human homologs, caspases-4 and −5. Caspase-11/4/5 bind directly to LPS, resulting in caspase-11/4/5 enzymatic cleavage of gasdermin-D (GSDMD). Cleaved GSDMD forms pores on the plasma membrane that results in cellular potassium (K+) efflux. K+ efflux is a signal detected by the cytosolic PRR, NLRP3, which then seeds an inflammasome to activate caspase-1. Caspase-1, in turn, cleaves the cytokine pro-IL-1β into its bioactive form. Cleaved IL-1β is released extracellularly via GSDMD pores, or upon pyroptotic cell lysis when GSDMD pores overwhelm cellular repair mechanisms.
Figure 3.
Figure 3.. Mechanisms for cytosolic detection of PAMPs from phagosomal bacteria.
A. Bacteria contained within phagosomes can possess PAMPs, including but not limited to LPS, CDNs, or DNA, that are detectable by cytosolic sensors, in this example caspases-11/4/5, STING, or cGAS respectively. However, PAMPs with appreciable polarity, size, or charge are unable to passively diffuse across the phagosomal membrane and are thus physically separated from their cognate cytosolic PRRs. B. Phagosomal bacteria can express membrane-targeting toxins that can form pores on the phagosomal membrane to translocate PAMPs into the cytosol. In addition, these toxins could cause membranolysis to translocate PAMPs and/or the entire bacterium into the cytosol. C. Phagosomal bacteria can express type 3 or 4 secretion systems (T3/4SS), which can directly translocate PAMPs from inside bacteria to the host cytosol. These T3/4SS can also be sensed by the host, leading to recruitment of host proteins, like guanylate binding proteins (GBPs), with potential membranolytic activity, resulting in PAMP and/or bacterial translocation into the cytosol. D. Phagosomal PAMPs could also be translocated by host PAMP transporters expressed on the phagosomal membrane. Host proteins within the lumen of the phagosome that have intrinsic membranolytic activities (e.g., HMGB1, neutrophil elastase, or LL-37) may also assist in PAMP translocation into the cytosol.
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