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

Ragland, Stephanie A.; Kagan, Jonathan C.

doi:10.1111/mmi.14841

Cited by 15 publications

(12 citation statements)

References 118 publications

(158 reference statements)

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“…Non-canonical inflammasome signaling results upon exposure of gram-negative bacterial lipopolysaccharide (LPS) to cytosolic caspase-11 (caspase-4 and -5 in humans) [ 25 , 56 , 57 ] ( Figure 2 ). Guanylate-binding proteins (GBPs) are not only proposed to mediate the lysis of vacuole membranes containing bacteria [ 58 , 59 ] and facilitate the disruption of cytosolic pathogen membranes [ 60 , 61 ], but have been shown to present LPS to caspase-11/4/5 by behaving as polyvalent signaling platforms [ 62 ]. Specifically, GBP1 appears to initiate platform assembly through electrostatic association with LPS or cytosolic Salmonella , with GBP2 and 4 being suggested as mediators, while GBP3 likely governs caspase activation [ 61 , 63–65 ].…”

Section: A Conventional Look At Pyroptosis: Canonical and Non-canonic...mentioning

confidence: 99%

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

Weir

Vince

2022

Biochemical Journal

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For over 15 years the lytic cell death termed pyroptosis was defined by its dependency on the inflammatory caspase, caspase-1, which, upon pathogen sensing, is activated by innate immune cytoplasmic protein complexes known as inflammasomes. However, this definition of pyroptosis changed when the pore-forming protein gasdermin D (GSDMD) was identified as the caspase-1 (and caspase-11) substrate required to mediate pyroptotic cell death. Consequently, pyroptosis has been redefined as a gasdermin-dependent cell death. Studies now show that, upon liberation of the N-terminal domain, five gasdermin family members, GSDMA, GSDMB, GSDMC, GSDMD and GSDME can all form plasma membrane pores to induce pyroptosis. Here, we review recent research into the diverse stimuli and cell death signaling pathways involved in the activation of gasdermins; death and toll-like receptor triggered caspase-8 activation of GSDMD or GSMDC, apoptotic caspase-3 activation of GSDME, perforin-granzyme A activation of GSDMB, and bacterial protease activation of GSDMA. We highlight findings that have begun to unravel the physiological situations and disease states that result from gasdermin signaling downstream of inflammasome activation, death receptor and mitochondrial apoptosis, and necroptosis. This new era in cell death research therefore holds significant promise in identifying how distinct, yet often networked, pyroptotic cell death pathways might be manipulated for therapeutic benefit to treat a range of malignant conditions associated with inflammation, infection and cancer.

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Section: A Conventional Look At Pyroptosis: Canonical and Non-canonic...mentioning

confidence: 99%

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

Weir

Vince

2022

Biochemical Journal

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“…In some instances, this is due to pathogen-concerted mechanisms, such as cell penetrating peptides or secretion systems and toxins, that allow for cytosolic invasion. These processes will not be discussed here as it has been recently reviewed elsewhere [see (63)(64)(65)(66)]. Instead, we discuss the emerging evidence for the active or phagocyte-concerted transfer of endocytosed PAMPs to the cytosol.…”

Section: Other Macromolecular "Danger" Signals That Are Delivered To ...mentioning

confidence: 99%

The Delivery of Extracellular “Danger” Signals to Cytosolic Sensors in Phagocytes

Gonzales

Canton

2022

Front. Immunol.

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Phagocytes, such as macrophages and dendritic cells, possess the ability to ingest large quantities of exogenous material into membrane-bound endocytic organelles such as macropinosomes and phagosomes. Typically, the ingested material, which consists of diverse macromolecules such as proteins and nucleic acids, is delivered to lysosomes where it is digested into smaller molecules like amino acids and nucleosides. These smaller molecules can then be exported out of the lysosomes by transmembrane transporters for incorporation into the cell’s metabolic pathways or for export from the cell. There are, however, exceptional instances when undigested macromolecules escape degradation and are instead delivered across the membrane of endocytic organelles into the cytosol of the phagocyte. For example, double stranded DNA, a damage associated molecular pattern shed by necrotic tumor cells, is endocytosed by phagocytes in the tumor microenvironment and delivered to the cytosol for detection by the cytosolic “danger” sensor cGAS. Other macromolecular “danger” signals including lipopolysaccharide, intact proteins, and peptidoglycans can also be actively transferred from within endocytic organelles to the cytosol. Despite the obvious biological importance of these processes, we know relatively little of how macromolecular “danger” signals are transferred across endocytic organelle membranes for detection by cytosolic sensors. Here we review the emerging evidence for the active cytosolic transfer of diverse macromolecular “danger” signals across endocytic organelle membranes. We will highlight developing trends and discuss the potential molecular mechanisms driving this emerging phenomenon.

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“…Cytosolic innate immune receptors play critical roles in host defense by sensing microbial products that access the cell interior and activating potent immune and inflammatory responses ( 1, 2 ). These receptors include several nucleic acids sensors, such as cGAS, RIG-I, NLRP1 and AIM2, as well as others that respond to bacterial products (NOD1/2, NAIPs/NLRC4) or danger signals (NLRP1/3) ( 2–7 ).…”

Section: Introductionmentioning

confidence: 99%

Methotrexate inhibition of muropeptide transporter SLC46A2 controls psoriatic skin inflammation

Bharadwaj

Lusi

Mashayekh

et al. 2022

Preprint

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Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here we focus on Slc46a2, which is highly expressed in mammalian epidermal keratinocytes, and show that it is critical for delivery of DAP-muropeptides and activation of NOD1 in keratinocytes, while the related transporter Slc46a3 is critical for responding to MDP, the NOD2 ligand. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, while methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively these studies define SLC46A2 as a transporter of NOD1 activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.

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

Cited by 15 publications

References 118 publications

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death

The Delivery of Extracellular “Danger” Signals to Cytosolic Sensors in Phagocytes

Methotrexate inhibition of muropeptide transporter SLC46A2 controls psoriatic skin inflammation

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