Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages

Franchi, Luigi; Amer, Amal O.; Body-Malapel, Mathilde; Kanneganti, Thirumala‐Devi; Özören, Nesrin; Jagirdar, Rajesh; Inohara, Naohiro; Vandenabeele, Peter; Bertin, John; Coyle, Anthony J.; Grant, Ethan P.; Núñez, Gabriel

doi:10.1038/ni1346

Cited by 1,045 publications

(1,068 citation statements)

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“…They could show that S. typhimurium with a deficient flagellin does not stimulate caspase-1 or IL-1b secretion, and that intracellular flagellin activates an IPAF inflammasome, 100,101 a mechanism that does not require the other flagellin sensor TLR5. 100,101 Similarly, other studies showed that NAIP5, a mouse parologue of NAIP, possibly in combination with IPAF, recognizes intracellular flagellin from Legionella pneumophila, in order to induce caspase-1 activation. 61,102,103 Moreover, early genetic studies in mice clearly identified NAIP5 as a L. pneumophila susceptibility locus, further delineating the importance of inflammatory caspases in the control of bacterial pathogens.…”

Section: Intracellular Flagellin: Detection By the Nlr Proteins Naip mentioning

confidence: 90%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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Fifteen years have passed since the cloning and characterization of the interleukin-1b-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction. Inflammatory CaspasesThe history of caspases began with the identification of an aspartate-specific protease activity involved in the conversion of the 31 kDa proIL-1b precursor to its active 17 kDa biologically active form, 1,2 and the identification of caspase-1 as the protease responsible for proIL-1b maturation. 3,4 The subsequent discovery of ced-3, that shares similarities with caspase-1 and which is involved in programmed cell death (PCD) in Caenorhabditis elegans, suggested that caspases might play fundamental roles in apoptosis. 5 As reviewed in the papers accompanying this issue of Cell Death and Differentiation, the role of apoptotic caspases in C. elegans and in vertebrates is crucial and deal with many facets of cell biology, development and diseases. In this review, we will focus on a subset of caspases present only in vertebrates and known as inflammatory caspases.Inflammatory caspases (also known as group I caspases) are encoded by three main genes in humans caspase-1, caspase-4 and caspase-5 and three main genes in mouse, caspase-1, caspase-11 and caspase-12. 6,7 In mammals, these caspases are characterized by the presence of a CARD domain at the N-terminus (Figure 1a). Human, chimp and mouse inflammatory caspases share significant similarity and are organized in a single locus (Figure 1c). Phylogenetic analysis of the conserved CARD domain suggests that the inflammatory caspases can be separated in evolutionaryrelated clusters (Figure 1b). The caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspase-1-like genes are absent in the mouse genome, suggesting that they have arisen recently by duplication of caspase-1. Although human and mouse caspase-1 are likely orthologues, sequence analysis suggests that human caspase-4 and caspase-5 have originated from a duplication of caspase-11. 7 However, the human caspase-12 gene, which in the chimp genome contains an SHG box important for it enzymatic activity, 8 evolved towards an enzymatically inactive form at some stage...

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Section: Intracellular Flagellin: Detection By the Nlr Proteins Naip mentioning

confidence: 90%

Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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“…Furthermore, flagellin appears to bind directly to TLR5 at residues 386-407, as TLR5 mutants lacking this domain are unable to interact with flagellin in biochemical assays (Mizel et al, 2003). Recent articles have demonstrated TLR5-independent recognition of cytosolic Salmonella typhimurium flagellin via Ipaf, a member of the NOD-LRR family (Franchi et al, 2006;Miao et al, 2006). Ipaf-mediated recognition of cytosolic flagellin induces caspase-1 activation and subsequent IL-1b secretion by macrophages.…”

Section: Bacterial Recognitionmentioning

confidence: 99%

NF-κB and the immune response

2006

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“…Thus, activation of NLRC4 requires a two-hit process to induce IL-1β secretion: the first hit is the induction of pro-IL-1β and pro-IL-18 synthesis through activation of Toll-like receptor (TLR), and the second hit is the initiation of inflammasome assembly, which initiates caspase-1 self-cleavage and formation of the active heterotetrameric caspase-1. This cysteine-aspartic acid protease activates several proteins, including pro-IL-1β and pro-IL-18, and induces the secretion of both cytokines [24]. …”

Section: Introductionmentioning

confidence: 99%

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

et al. 2018

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B cells are a target of Salmonella infection, allowing bacteria survival without inducing pyroptosis. This event is due to downregulation of Nlrc4 expression and lack of inflammasome complex activation, which impairs the secretion of IL-1β. YAP phosphorylation is required for downregulation of Nlrc4 in B cells during Salmonella infection; however, the microorganism’s mechanisms underlying the inhibition of the NLRC4 inflammasome in B cells are not fully understood. Our findings demonstrate that the Salmonella effector SopB triggers a signaling cascade involving PI3K, PDK1 and mTORC2 that activates Akt with consequent phosphorylation of YAP. When we deleted sopB in Salmonella, infected B cells that lack Rictor, or inhibited the signaling cascade using a pharmacological approach, we were able to restore the function of the NLRC4 inflammasome in B cells and the ability to control the infection. Furthermore, B cells from infected mice exhibited activation of Akt and YAP phosphorylation, suggesting that Salmonella also triggers this pathway in vivo. In summary, our data demonstrate that the Salmonella effector inositide phosphate phosphatase SopB triggers the PI3K-Akt-YAP pathway to inhibit the NLRC4 inflammasome in B cells. This study provides further evidence that Salmonella triggers cellular mechanisms in B lymphocytes to manipulate the host environment by turning it into a survival niche to establish a successful infection.

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Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages

Cited by 1,045 publications

References 45 publications

Inflammatory caspases and inflammasomes: master switches of inflammation

Inflammatory caspases and inflammasomes: master switches of inflammation

NF-κB and the immune response

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

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