Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation

Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase-1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K (+) efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca (2+) fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation

Neurotoxic phospholipase A2 from rattlesnake as a new ligand and new regulator of prokaryotic receptor GLIC (proton-gated ion channel from G. violaceus)

International audienceNeurotoxic phospholipases A2 (sPLA2) from snake venoms interact with various protein targets with high specificity and potency. They regulate function of multiple receptors or channels essential to life processes including neuronal or neuromuscular chemoelectric signal transduction. These toxic sPLA2 exhibit high pharmacological potential and determination of PLA2-receptor binding sites represents challenging part in the receptor-channel biochemistry and pharmacology. To investigate the mechanism of interaction of neurotoxic PLA2 with its neuronal receptor at the molecular level, we used as a model crotoxin, a heterodimeric sPLA2 from rattlesnake venom and proton-gated ion channel GLIC, a bacterial homolog of pentameric ligand-gated ion channels. The three-dimensional structures of both partners, crotoxin and GLIC have been solved by X-ray crystallography and production of full-length pentameric GLIC (with ECD and TM domains) is well established. In the present study, for the first time, we demonstrated physical and functional interaction of full-length purified and solubilized GLIC with CB, (PLA2 subunit of crotoxin). We identified GLIC as a new protein target of CB and CB as a new ligand of GLIC, and showed that this non covalent interaction (PLA2-GLIC) involves the extracellular domain of GLIC. We also determined a novel function of CB as an inhibitor of proton-gated ion channel activity. In agreement with conformational changes observed upon formation of the complex, CB appears to be negative allosteric modulator (NAM) of GLIC. Finally, we proposed a possible stoichiometric model for CB - GLIC interaction based on analytical ultracentrifugation

Coordination and expertise foster legal textualism

Funding Information: ACKNOWLEDGMENTS. This research was supported by the Spanish Ministry of Science and Innovation (PID2020-119791RA-I00; RTI2018-098882-B-I00), the Polish National Science Centre (2020/36/C/HS5/00111; 2017/25/N/HS5/00944), the Swiss National Science Foundation (PZ00P1_179912), and the European Research Council (805498). Publisher Copyright: Copyright © 2022 the Author(s).A cross-cultural survey experiment revealed a dominant tendency to rely on a rule’s letter over its spirit when deciding which behaviors violate the rule. This tendency varied markedly across (k = 15) countries, owing to variation in the impact of moral appraisals on judgments of rule violation. Compared with laypeople, legal experts were more inclined to disregard their moral evaluations of the acts altogether and consequently exhibited stronger textualist tendencies. Finally, we evaluated a plausible mechanism for the emergence of textualism: in a two-player coordination game, incentives to coordinate in the absence of communication reinforced participants’ adherence to rules’ literal meaning. Together, these studies (total n = 5,794) help clarify the origins and allure of textualism, especially in the law. Within heterogeneous communities in which members diverge in their moral appraisals involving a rule’s purpose, the rule’s literal meaning provides a clear focal point—an identifiable point of agreement enabling coordinated interpretation among citizens, lawmakers, and judges.Peer reviewe