Caspase-1 and Gasdermin D Afford the Optimal Targets with Distinct Switching Strategies in NLRP1b Inflammasome-Induced Cell Death

Abstract

Inflammasomes are essential complexes of innate immune system, which form the first line of host defense against pathogens. Mounting evidence accumulates that inflammasome signaling is highly correlated with coronavirus disease 2019 (COVID-19). However, there remains a significant gap in our understanding of the regulatory mechanism of inflammasome signaling. Combining mathematical modeling with experimental analysis of NLRP1b inflammasome signaling, we found that only the expression levels of caspase-1 and GSDMD have the potential to individually switch cell death modes. Reduction of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Caspase-1 and GSDMD present different thresholds and exert distinct pathway choices in switching death modes. Pyroptosis switches to apoptosis with an extremely low threshold level of caspase-1, but with a high threshold of GSDMD. Caspase-1-impaired cells employ ASC-caspase-8-dependent pathway for apoptosis, while GSDMD-impaired cells primarily utilize caspase-1-dependent pathway. Additionally, caspase-1 and GSDMD can severally ignite the cooccurrence of pyroptosis and apoptosis. Landscape topography unravels that the cooccurrence is dramatically different in caspase-1- and GSDMD-impaired cells. Besides pyroptosis state and apoptosis state, a potential new “coexisting” state in single cells is proposed when GSDMD acts as the driving force of the landscape. The “seesaw model” is therefore proposed, which can well describe the death states that are controlled by caspase-1 or GSDMD in single cells. Our study sheds new light on NLRP1b inflammasome signaling and uncovers the switching mechanisms among various death modes, providing potential clues to guide the development of more rational control strategies for diseases.

Dear-DIAXMBD: deep autoencoder for data-independent acquisition proteomics

“…We also benchmarked Dear-DIA XMBD on TNFR1 (tumor necrosis factor receptor 1) complex dataset 23, 47, 48, 49 from L929 cells treated with TNF from six different time periods. We performed a comparison of OpenSWATH quantified results and manual inspection results, showing that Dear-DIA XMBD can find truly regulated proteins ( Supplementary Fig.…”

Mathematical Models of Death Signaling Networks

“…ODE and Boolean logic-based approaches are the most common mathematical techniques used to model cell death mechanisms. However, a physical description based on the potential landscape theory has been recently applied to study stochastic dynamics and global stability of cell death signaling pathways [ 8 , 73 ]. In this approach, the steady state probability distribution of a system P ss and a dimensionless potential function E are related via Boltzmann relation: E = −ln( P ss ) [ 91 ].…”

“…Currently, the molecular mechanism that regulates the selection of each specific death execution pathway remains elusive. In addition, mathematical models developed to study crosstalk between necroptosis and apoptosis [ 65 ], pyroptosis and apoptosis [ 73 ], autophagy and apoptosis [ 29 ] support the hypothesis that signals propagating through different cell death pathways are integrated to process the execution of specific cell death. We are developing a mathematical model of the cell death decision network to predict the molecular species and interactions that direct the signal flow towards a specific irreversible cell death fate.…”

“…Li et al extended the GSDMD-induced pyroptosis model by adding apoptosis regulation [ 73 ]. The model allows one to study the crosstalk between pyroptosis and apoptosis and inflammasome-induced cell death under different perturbation conditions.…”

Molecular Mechanisms of Inflammasome in Ischemic Stroke Pathogenesis

“…The maturation and increase of IL-1β and IL-18 cytokines, that play a pivotal role in neuroinflammation, depend on activating the NLRP3/caspase-1 axis [ 25 ]. Furthermore, caspase 1 is capable of inducing both apoptosis and pyroptosis, a particular type of cell death [ 44 ].…”