Laboratory of Innate Immunity and Cell Death Publication


NLRC4 Deficiency Leads to Enhanced Phosphorylation of MLKL and Necroptosis
Sundaram B.; Karki R.; Kanneganti T.-D.
Immuno Horizons
2022 Mar
50_2022_NLRC4 Deficiency Leads to Enhanced Phosphorylation of MLKL and Necroptosis.pdf (1.6M) 10회 다운로드 DATE : 2023-12-29 15:19:51


Hosts rely on the innate immune system to clear pathogens in response to infection. Pathogen-associated molecular patterns (PAMPs) bind to innate immune receptors and engage activation of downstream signaling to initiate a host immune response to fight infection. A key component of this innate response is programmed cell death (PCD). Recent work has highlighted significant crosstalk and functional redundancy between cell death pathways, leading to the discovery of PANoptosis, an inflammatory PCD pathway dependent on PANoptosomes, which are innate immune danger sensing complexes that activate inflammatory cell death and contain caspase(s) with or without inflammasome components and RHIM-containing proteins. While PANoptosis has been characterized in response to a growing number of pathogens, inflammatory diseases and cancer, its role and the functional consequences of PANoptotic component modulation during NLRC4 activation by Pseudomonas aeruginosa infection remain unknown. Here, we show that P. aeruginosa can induce PANoptosis in mouse bone marrow-derived macrophages (BMDMs). Only the combined deletion of caspase-1, -11, -8, and RIPK3 protected mouse BMDMs from cell death. Moreover, we showed that PANoptotic components act in a compensatory manner; in the absence of NAIP5 and NLRC4 during P. aeruginosa challenge, alternative cell death molecules such as RIPK1 and MLKL were activated, while activation of caspase-1, -3, -7, and -8 were reduced in mouse BMDMs. Together, these data highlight the extensive crosstalk between cell death signaling molecules and showcase the plasticity of the system. 

Keywords: NAIP5, NLRC4, inflammasome, MLKL, PANoptosis, PANoptosome, Pseudomonas, caspase-1, caspase-8, caspase-3, caspase-7, gasdermin D, RIPK1, RIPK3