New insights in caspase-11 functions in noncanonical inflammasome signalling Mélanie Bodnar, Virginie Petrilli To cite this version: Mélanie Bodnar, Virginie Petrilli. New insights in caspase-11 functions in noncanonical inflammasome signalling. Inflammasome, De Gruyer, 2014, 10.2478/infl-2014-0001. hal-02376149 HAL Id: hal-02376149 https://hal.archives-ouvertes.fr/hal-02376149 Submitted on 22 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. DOI: 10.2478/infl-2014-0001 Inflammasome 2014; volume 1: 20–26 Minireview Open Access Mélanie Bodnar, Virginie Petrilli New insights in caspase-11 functions in noncanonical inflammasome signalling Abstract: Inflammasomes are multi-protein complexes Patterns (PAMPs) and Danger Associated Molecular that play a crucial role in innate immunity. They are Patterns (DAMPs), which are released after cellular stress assembled by cytosolic sensors of the Nucleotide-binding or damage. PRRs trigger different cellular signalling domain and Leucine-rich repeat containing Receptor (NLR) pathways, resulting in inflammation. Key actors in this and PYrin and HIN (PYHIN) domain-containing protein immune surveillance are cytosolic protein complexes families upon sensing various pathogens and danger termed inflammasomes. Inflammasomes regulate the signals. Inflammasome formation culminates in caspase-1 activity of caspase-1, which subsequently controls the activation, which causes the cleavage of pro-IL-1β and pro- production of pro-inflammatory cytokines and cell IL-18 into active cytokines; this eventually results in the death. Although most of the research has focused on induction of an inflammatory cell death called pyroptosis. the prototype inflammatory caspase, caspase-1, recent Recent data using Gram-negative bacteria suggests a role data has highlighted major roles for caspase-11 in innate for caspase-11 not only in NLRP3 inflammasome activation immunity through its ability to modulate inflammasome but also in a caspase-1- and inflammasome-independent activation and cell death. cell death. This novel caspase-11-dependent pathway is critical to control infection by Gram-negative bacteria and has been named the noncanonical inflammasome. The inflammatory caspases in humans and mice Keywords: caspase-1, cell death, cytosolic LPS, IL-1b, inflammasome Caspases are cysteine proteases synthesized as inactive zymogens requiring proteolytic processing for activation. They can be subdivided into two groups, apoptotic caspases *Corresponding author: Virginie Petrilli: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France and inflammatory caspases [1]. Whereas apoptotic Université de Lyon, F-69000 Lyon, France, virginie.petrilli@lyon. caspases are well conserved throughout evolution, unicancer.fr inflammatory caspases are less conserved as they appear Mélanie Bodnar and Virginie Petrilli: INSERM U1052, Centre de in the vertebrate lineage [2]. Inflammatory caspases play a Recherche en Cancérologie de Lyon, F-69000 Lyon, France prominent role in innate immunity. In Homo sapiens (Hs), Université de Lyon, F-69000 Lyon, France the main inflammatory caspases consist of caspase-1, -4, Université Lyon 1, ISPB, Lyon, F-69622, France, F-69000 Lyon, France CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, and -5 (hcaspase-12 carries mutation giving rise to a non- F-69000 Lyon, France functional enzyme), while in Mus musculus (Mm) there are Centre Léon Bérard, F-69008 Lyon, France caspase-1, -11 and -12 (Figure 1) [3,4]. In both species these caspases are located within the same locus, chromosome 11q22 for Hs and chromosome 9A1 for Mm. Genetic Introduction analysis suggested that human and mouse caspase-1 are orthologues whereas caspase-4 and -5 could originate An efficient immune response depends on the from the duplication of a caspase-11-like ancient gene [5]. inflammatory cascade that is orchestrated by the innate The major substrates of the inflammatory caspase-1 immune system. Innate immunity relies on the activity are pro-Interleukin-1β (pro-IL-1β) and pro-IL-18, two of germline-encoded Pathogen Recognition Receptors important pro-inflammatory cytokines. Inflammatory (PRRs) in surveying the extracellular and intracellular caspases are mainly initiator caspases. Like apoptotic space for any signs of pathogen invasion or tissue initiator caspases, they exhibit a death fold-containing injury. These sensors detect highly conserved motifs in CARD prodomain (Caspase Activation and Recruitment pathogens, known as Pathogen Associated Molecular Domain) suggesting their recruitment and activation © 2014 Mélanie Bodnar, Virginie Petrilli, licensee De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial- NoDerivs 3.0 License. Unauthenticated Download Date | 11/6/14 9:51 PM New insights in caspase-11 functions in noncanonical inflammasome signalling 21 a. Ini$ators of apoptosis Caspase-­‐2 CARD L S Caspase-­‐9 CARD L S Caspase-­‐8 DED DED L S human Caspase-­‐10 DED DED L S Effectors of apoptosis Caspase-­‐3 L S Caspase-­‐6 L S human Caspase-­‐7 L S Inflammatory caspases Caspase-­‐1 CARD L S Caspase-­‐4 CARD L S human Caspase-­‐5 CARD L S Caspase-­‐1 CARD L S Caspase-­‐11 CARD L S mouse Caspase-­‐12 CARD L S b. Apopto$c caspases Caspase-­‐4 (Homo sapiens) Caspase-­‐5 (Homo sapiens) Caspase-­‐11 (Mus musculus) Caspase-­‐12 (Mus musculus) Caspase-­‐1 (Homo sapiens) caspases Inflammatory Caspase-­‐1 (Mus musculus) Figure 1: Overview of apoptotic and inflammatory caspases. (a) Schematic view of the structural organisation of human apoptotic and inflammatory caspases; L, large subunit, S, short subunit. CARD, Caspase Activation and Recruitment Domain, DED, Death Effector Domain. * non functional in human. (b) Phylogenic analysis of mouse and human inflammatory caspases based on full sequences. within multiprotein complexes. Among inflammatory the inflammation field with new functions, which will be caspases, caspase-1 is the only member whose activation described below. within a molecular platform, the inflammasome, has been well-documented [6]. Little is known about the modes of activation, functions, and substrates of caspase-4, General overview of the -5, -11 and -12. Caspase-5 was proposed to be part of the inflammasomes inflammasome, but little work has corroborated this early observation [6]. Recent studies using different caspase-12- The term inflammasome was first proposed in 2002 by deficient mouse models led to conflicting observations. Martinon and Tschopp to describe a caspase-1-activating Although some data suggested that caspase-12 may platform resulting from the assembly of a protein complex participate in endoplasmic reticulum stress-induced that includes the PRR NLRP1 [6]. Since then, different NLR apoptosis, other studies suggested it acts as a negative (e.g. NLRP3, NLRC4, NLRP6, NLRP12) and PYHIN (AIM2) regulator of inflammation by impairing caspase-1 function family members have been shown to form inflammasomes [7,8]. Before 2011, little was known about caspase-11 [10-15]. The human NLR family is composed of twenty- function in inflammation except that it participates in two members sharing a similar structural organisation: the inflammatory response by controlling caspase-1 a N-terminal interacting domain, followed by a central activation upon lipopolysaccharide (LPS) stimulation Nucleotide Oligomerization Domain (NOD) and a C-terminus [9]. Since then, caspase-11 has emerged as a new focus in Leucine-Rich Repeat (LRR) motif. The LRRs behave as a Unauthenticated Download Date | 11/6/14 9:51 PM 22 Mélanie Bodnar, Virginie Petrilli sensing module and interact with NOD to keep the receptor caspase-11 in sensitive strains such as C57BL/6. Although in an inactive monomeric state [16,17]. Most PRRs involved many research laboratories work with C57BL/6 caspase-1 in inflammasome formation contain at their N-terminus a knockout (KO) colonies, the ES cells used in the past PYD (in the case of NLRPs and AIM2) or a CARD domain to generate knockout mice originate from 129 strains. (in the case of NLRC4). Once oligomerized, the scaffolding These strains appear to carry inactivating mutations in receptors recruit the adaptor protein, Apoptosis-associated the caspase-11 locus resulting in the absence of caspase- Speck-like protein containing a CARD (ASC), which recruits 11 protein. As caspase-1 and caspase-11 are adjacent on caspase-1 molecules, resulting in a local increase in the mouse chromosome 9, it is unlikely that these genes caspase-1 concentration and activation. NLRC4 contains a could segregate by recombination upon backcrossing. CARD domain that can directly interact with caspase-1 to Therefore, the caspase-1 KO mice used thus far in all induce cell death. However, ASC is required for efficient studies are casp1/11 double KO [34,35]. NLRC4-dependent caspase-1 auto-processing and IL-1β The use of macrophages isolated from the secretion [11,18-20]. C57BL/6 caspase-11- or caspase-1/11-deficient mice Inflammasomes assemble in the cytosol in a stimulus- complemented