Caspase-11 Promotes the Fusion of Phagosomes Harboring Pathogenic Bacteria with Lysosomes by Modulating Actin Polymerization

Akhter, Anwari; Caution, Kyle; Khweek, Arwa Abu; Tazi, Mia; Abdulrahman, Basant; Abdelaziz, Dalia H.; Voß, Oliver; Doseff, Andrea I.; Hassan, Hesham; Azad, Abul K.; Schlesinger, Larry S.; Wewers, Mark D.; Gavrilin, Mikhail A.; Amer, Amal O.

doi:10.1016/j.immuni.2012.05.001

Cited by 168 publications

(274 citation statements)

References 57 publications

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“…Cleaved CASP7, as a result of CASP1 activation, has been described for S . Typhimurium [29], L. pneumophila [30] and B. pseudomallei [39] infection, all of which are pathogens predominantly sensed by the NLRC4 inflammasome [16]. Thus, our results demonstrate that CASP1-dependent CASP7 activation is not restricted to the NLRC4 inflammasome.…”

Section: Discussionmentioning

confidence: 75%

“…CASP4 restricts the growth of L. pneumophila , an intracellular pathogen that resides in autophagosomes in WT macrophages [3,16,25]. Notably, B. cenocepacia is also cleared by autophagosomes in healthy macrophages [5], but the role of CASP4 in intracellular trafficking of this bacterium is not known.…”

Section: Resultsmentioning

confidence: 99%

“…Microtubules and actin filaments provide a scaffold to allow vesicular trafficking, and remodeling of the actin cytoskeleton involves CASP4 [16,25,36]. Depolymerization of actin filaments specifically inhibits starvation-induced autophagosome formation, indicating a critical role for actin during the early stages of autophagy [37].…”

Section: Resultsmentioning

confidence: 99%

“…Although, CASP4 has been implicated in the restriction of L. pneumophila and the closely related Burkholderia species B. pseudomallei and B. thailandensis , the exact mechanism is still unclear [16,38]. Recognition of intracellular B. cenocepacia in murine macrophages is mediated through NOD-like receptors including NLRP3 and MEFV/PYRIN [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…However, during L. pneumophila infection, inflammasome activation promotes autophagy [24]. Specifically, CASP4 activity modulates actin polymerization in L. pneumophila -infected macrophages, and hence facilitates the trafficking of phagosomes to lysosomal compartments for bacterial clearance [16,25]. Interestingly, transportation of phagosomes containing nonpathogenic Escherichia coli is not influenced by CASP4, suggesting differential regulation of endocytic pathways depending on the captured cargo [16].…”

Section: Introductionmentioning

confidence: 99%

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CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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CASP4/caspase-11-dependent inflammasome activation is important for the clearance of various Gram-negative bacteria entering the host cytosol. Additionally, CASP4 modulates the actin cytoskeleton to promote the maturation of phagosomes harboring intracellular pathogens such as Legionella pneumophila but not those enclosing nonpathogenic bacteria. Nevertheless, this non-inflammatory role of CASP4 regarding the trafficking of vacuolar bacteria remains poorly understood. Macroautophagy/autophagy, a catabolic process within eukaryotic cells, is also implicated in the elimination of intracellular pathogens such as Burkholderia cenocepacia. Here we show that CASP4-deficient macrophages exhibit a defect in autophagosome formation in response to B. cenocepacia infection. The absence of CASP4 causes an accumulation of the small GTPase RAB7, reduced colocalization of B. cenocepacia with LC3 and acidic compartments accompanied by increased bacterial replication in vitro and in vivo. Together, our data reveal a novel role of CASP4 in regulating autophagy in response to B. cenocepacia infection.

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Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

Krause¹,

Caution²,

Badr³

et al. 2018

Autophagy

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A bacterial protein promotes the recognition of the Legionella pneumophila vacuole by autophagy

et al. 2013

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Legionella pneumophila (L. pneumophila) is an intracellular bacterium of human alveolar macrophages that causes Legionnaires' disease. In contrast to humans, most inbred mouse strains are restrictive to L. pneumophila replication. We demonstrate that autophagy targets L. pneumophila vacuoles to lysosomes and that this process requires ubiquitination of L. pneumophila vacuoles and the subsequent binding of the autophagic adaptor p62/SQSTM1 to ubiquitinated vacuoles. The L. pneumophila legA9 encodes for an ankyrin-containing protein with unknown role. We show that the legA9 mutant is the first L. pneumophila mutant to replicate in wild-type (WT) mice and their bone marrow derived macrophages (BMDMs). Less legA9 mutant- containing vacuoles acquired ubiquitin labeling and p62/SQSTM1 staining, evading autophagy uptake and avoiding lysosomal fusion. Thus, we describe a bacterial protein that targets the L. pneumophila -containing vacuole for autophagy uptake.

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Caspase‐11: The driving factor for noncanonical inflammasomes

Viganò

Mortellaro

2013

Eur J Immunol

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Inflammasomes are large multiprotein platforms that mediate the processing of caspase-1, which in turn promotes the maturation and release of IL-1β and IL-18 in response to microbial and danger signals. While the canonical pathway of inflammasome activation has been known for some time, a novel mechanism of noncanonical inflammasome activation mediated by caspase-11 was more recently identified. This pathway engages caspase-11 to trigger both caspase-1-dependent and -independent production of the inflammatory cytokines IL-1β, IL-18, and IL-1α, as well as to promote pyroptosis, a form of genetically programmed cell death that is associated with the release of such cytokines. In this review, we gather together studies on both the mechanisms and implications of caspase-11-mediated noncanonical inflammasome activation, and discuss the emerging importance of this pathway in regulating host defense against intracellular bacterial pathogens.

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Caspase-11 Promotes the Fusion of Phagosomes Harboring Pathogenic Bacteria with Lysosomes by Modulating Actin Polymerization

Cited by 168 publications

References 57 publications

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

A bacterial protein promotes the recognition of the Legionella pneumophila vacuole by autophagy

Caspase‐11: The driving factor for noncanonical inflammasomes

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