Non-canonical activation of inflammatory caspases by cytosolic LPS in innate immunity
Introduction
Mammalian innate immunity relies on a family of pattern recognition receptors (PRRs) to detect conserved microbial molecules termed pathogen-associated molecular patterns (PAMPs) [1, 2]. PRRs engagements by corresponding PAMPs activate inflammatory pathways such as the nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) signaling for cytokine transcription and clearance of the infections. The PRR family includes Toll-like receptor (TLR), C-type lectin receptor (CLR), RIG-I-like receptor (RLR), AIM2-like receptor (ALR) and NLR containing a Nucleotide-binding domain (NBD) and a Leucine-rich Repeat (LRR) domain. TLR and CLR are localized on the plasma or endosomal membrane while RLR, ALR and NLR are cytoplasmic [3, 4]. These enable the host to monitor both extracellular and intracellular infections. The best studied PRR is TLR4 that complexes with MD2 to recognize LPS [4], the major component of Gram-negative bacteria cell wall. Identification of TLR4 as the LPS receptor is paradigm-shifting in innate immunity [5].
Several NLRs and ALR, in response to certain PAMPs, form a canonical inflammasome complex for activating caspase-1 [6, 7]. For example, the NAIP subfamily of NLRs, upon recognition of bacterial flagellin or type III secretion apparatus, undergoes hetero-oligomerization with an adaptor NLR (NLRC4) for inflammasome assembly [8, 9, 10]. Activated caspase-1 then processes interleukin (IL)-1β and IL-18 for their maturation and at the same time induces pyroptosis, a lytic form of inflammatory cell death. Caspase-1 belongs to the inflammatory caspase group that additionally includes murine caspase-11, human caspase-4 and caspase-5, and also caspase-12. These caspases structurally resemble apoptotic initiator caspases, all bearing an amino-terminal caspase-activation and recruitment domain (CARD). A recent study suggests that caspase-11 can also induce pyroptosis in response to bacterial infections in a caspase-1 independent manner [11]. Analogous to caspase-1 activation by canonical inflammasome scaffolds, a ‘non-canonical inflammasome’ for caspase-11 activation was proposed. Here we review research progresses on the ‘non-canonical inflammasome’ in the past two years.
Section snippets
LPS activation of a caspase-11 ‘non-canonical inflammasome’
In studying toxin stimulation of inflammasome responses, Kayagaki et al. observed that cholera toxin B (CTB) could induce NLRP3/ASC-dependent IL-1β maturation in LPS-primed mouse macrophages [11]. Surprisingly, this activation was absent in macrophages derived from strain 129 mice. The defect was attributed to the polymorphism in 129 mice-derived caspase-11 that encodes a truncated and nonfunctional caspase-11 protein. This led to the discovery of caspase-11 function in sensing CTB as well as
Direct recognition of LPS by caspase-11 and human caspase-4/caspase-5
Caspase-11 activation does not require the ASC adaptor [11]. A prevailing hypothesis then, according to knowledge learned from cell death and inflammation researches, was that an unknown CARD-containing protein serves as an intracellular LPS sensor and activates caspase-11 through CARD–CARD interaction. However, extensive efforts made in several research groups (including ours) to search for such hypothetic LPS sensor turned out to be fruitless [22••]. Meanwhile, we succeeded in reconstituting
LPS binding induces caspase-4/caspase-11 oligomerization and activation
Consistent with the oligomeric state of E. coli-purified caspase-4/caspase-11, LPS binding of monomeric caspase-4/caspase-11 or even the CARDs alone induced their oligomerization [22••] (Figure 1). As a result, caspase-4/caspase-11 became catalytic active in hydrolyzing the zVAD-AMC substrate. Mutations in several basic residues in the CARD of caspase-11, particularly Lys-19, which disrupted LPS binding, also inhibited LPS-induced caspase-11 oligomerization, activation as well as stimulation of
Regulation of inflammatory caspases sensing of LPS
LPS robustly stimulates caspase-11 transcription through the TLR4 signaling [17••, 18••, 26]. Other TLR agonists, such as polyinosinic–polycytidylic acid, and interferon (IFN)-β/γ could also induce caspase-11 expression [13, 14, 15•, 16, 27]. Given the low basal expression of caspase-11, transcriptional induction is important for macrophage sensing of intracellular LPS. Supporting this notion, the TRIF-IRF-IFN signaling was shown to be essential for caspase-11 activation by bacterial infections
Function of intracellular LPS sensing and LPS-induced sepsis
The molecular mechanism underlying caspase-4/caspase-5/caspase-11 activation-induced pyroptosis is unknown. The similar morphology between caspase-4/caspase-5/caspase-11 and caspase-1-mediated pyroptosis indicates a possible common death program involving proteolytic cleavage of certain cellular proteins. In host defense, caspase-1-mediated pyroptosis serves as an innate immune effector mechanism in clearing intracellular infection [33], and this probably also applies to LPS-induced
Conclusions and perspectives
A ‘non-canonical inflammasome’ for caspase-11 activation was originally proposed based on the high similarity between caspase-11 and caspase-1 [11]. Recent studies have not only identified cytoplasmic LPS being the agonist for the ‘non-canonical inflammasome’ [17••, 18••], but also revealed that inflammatory caspases (caspase-4/caspase-5/caspase-11) themselves are direct sensors for LPS [22••]. Cytosolic recognition of LPS induces caspase oligomerization and activation, thereby triggering cell
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologize to colleagues whose work could not be cited due to space limitation. We thank M. Shi for preparing the artwork. Work in the authors’ laboratory was supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute and the Beijing Scholar Program to F.S. The work was also supported by the National Basic Research Program of China 973 Programs (2012CB518700 and 2014CB849602), the Strategic Priority Research Program of the Chinese Academy of
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