The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Abstract

Inflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasomeindependent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.

NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway

“…The structure of NLRC4 without the CARD domain revealed that the inactive conformation of NLRC4 is stabilized by the adenosine diphosphate, which interacts with residues located in NBD and WHD 17 , 19 . Additionally, the HD-2 and LRR domains interact with the NBD domain, further locking NLRC4 into the inactive conformation and preventing NLRC4 oligomerization 17 , 19 . If similar stabilization with a presumably negligible effect of interactions with PYD is provided for NLRP3, then replacing the PYD for the CARD domains of either NLRC4 or ASC should result in NLRP3 trigger-dependent inflammasome assembly.…”

“…NLRC4 has a fascinating feature that upon activation with a bacterial ligand the ligand-NAIP complex engages additional NLRC4 molecules in a prion-like seeded polymerization event 20 – 22 , resulting in inflammasome complexes where NLRC4 molecules greatly outnumber the NAIP/bacterial trigger complexes. Apoptosomes, which are also caspase-activating platforms, self-assemble in a stoichiometric manner (reviewed in 19 ). Thus far, it has been unknown whether NLRP3 is activated through the oligomerization of activated, multiple open conformation NLRP3 molecules (Fig.…”

“…Molecular structures of homologous proteins NLRC4 17 and NLRC2 18 in an inactive conformation were determined, advancing the structural knowledge of NLRs. The structure of mouse NLRC4 lacking the N-terminal CARD domain reveals that autoinhibition is provided by extensive intramolecular interactions between different domains and interactions with ADP 17 (reviewed in 19 ). There are substantial structural differences between NLRC4 and NLRC2, mostly in the HD2 domain and its orientation toward the NBD-HD1-WHD 18 .…”

Genotoxicity of amorphous silica nanoparticles: Status and prospects

“…NLRP3 inflammasome, a complex of proteins assembled in the cytosol, plays a critical role in the secretion of cytokines of interleukin 1 (IL-1) family which includes IL-1β, IL-18, and IL-33. 135,136 Many fibrous, cationic and crystalline nanoparticles activate NLRP3 inflammasome through lysosomal damage. [137][138][139] Such damage occurs as a result of either mechanical disruption (e.g., in the case of titanium nanobelts) 137 or proton-sponge effects (e.g., cationic liposomes).…”

Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

“…IL-1β production by immune cells requires two signals, priming and activation. The priming initiated by pattern recognition receptors (PRRs) upon recognition of pathogen-associated molecular patterns (PAMPs) leads to transcription of IL-1β and related genes in NF-κB (8) and STAT3 (9) dependent pathways and production of pro-IL-1β and inflammasome components; the activation provided by intracellular PRRs and damage-associated molecular patterns (DAMPs) initiates the assembly of inflammasome and activation of caspase-1 which cleaves pro-IL-1β into mature IL-1β (8) and cleaves gasdermin D to form cellular membrane pores for the release of mature IL-1β (10). Inflammasomes are activated by either PAMPs or DAMPs directly (11) or indirectly through P2×7 receptor (12).…”