CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability

Kapplusch, Franz; Schulze, Felix; Rabe-Matschewsky, Sabrina; Ruß, Susanne; Herbig, Maik; Heymann, Michael C.; Schoepf, Katharina; Stein, Robert; Range, Ursula; Rösen‐Wolff, Angela; Winkler, Stefan; Hedrich, Christian M.; Guck, Jochen; Hofmann, Sigrun R.

doi:10.1016/j.clim.2019.06.008

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…The fact that we observed a burden of CASP1 rare variants with IL-6 production and not with IL-1β is surprising, as CASP-1 protein is most known for cleavage of the inactive mediators IL-1β, IL-18, and IL-33 into their active form [2]. However, abnormal pyroptosome formation and impaired nuclear localization independent of the enzymatic activity of CASP-1 in processing pro-IL1β into active IL1β was previously observed [51]. Importantly, in our allelic score follow-up, we were unable to detect a significant correlation, suggesting that this association was mainly driven by a single individual with extremely low IL-6 cytokine production (Additional file 2: Fig.…”

Section: Discussionsupporting

confidence: 50%

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

et al. 2021

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Background The interleukin (IL)-1 pathway is primarily associated with innate immunological defense and plays a major role in the induction and regulation of inflammation. Both common and rare genetic variation in this pathway underlies various inflammation-mediated diseases, but the role of rare variants relative to common variants in immune response variability in healthy individuals remains unclear. Methods We performed molecular inversion probe sequencing on 48 IL-1 pathway-related genes in 463 healthy individuals from the Human Functional Genomics Project. We functionally grouped common and rare variants, over gene, subpathway, and inflammatory levels and performed the Sequence Kernel Association Test to test for association with in vitro stimulation-induced cytokine responses; specifically, IL-1β and IL-6 cytokine measurements upon stimulations that represent an array of microbial infections: lipopolysaccharide (LPS), phytohaemagglutinin (PHA), Candida albicans (C. albicans), and Staphylococcus aureus (S. aureus). Results We identified a burden of NCF4 rare variants with PHA-induced IL-6 cytokine and showed that the respective carriers are in the 1% lowest IL-6 producers. Collapsing rare variants in IL-1 subpathway genes produces a bidirectional association with LPS-induced IL-1β cytokine levels, which is reflected by a significant Spearman correlation. On the inflammatory level, we identified a burden of rare variants in genes encoding for proteins with an anti-inflammatory function with S. aureus-induced IL-6 cytokine. In contrast to these rare variant findings which were based on different types of stimuli, common variant associations were exclusively identified with C. albicans-induced cytokine over various levels of grouping, from the gene, to subpathway, to inflammatory level. Conclusions In conclusion, this study shows that functionally grouping common and rare genetic variants enables the elucidation IL-1-mediated biological mechanisms, specifically, for IL-1β and IL-6 cytokine responses induced by various stimuli. The framework used in this study may allow for the analysis of rare and common genetic variants in a wider variety of (non-immune) complex phenotypes and therefore has the potential to contribute to better understanding of unresolved, complex traits and diseases.

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Section: Discussionsupporting

confidence: 50%

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

et al. 2021

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“…Procaspase-1 translocation to the nucleus is mediated by an NLS mapped to the amino acids 4 to 11 at the N -terminal caspase-1 recruitment domain (CARD) [ 33 ]. In addition, mutation of L265S (leucine changed to serine at amino acid 265) impairs nuclear localization of pro-caspase-1 [ 74 ], suggesting that the amino acid 265 at p20 of active caspase-1 also plays a role in localizing caspase-1 to the nucleus. However, the molecular mechanisms that are responsible for nuclear accumulation of pro-caspase-1 had not been identified yet; and the question of whether pro-caspase-1 has the ability to translocate from nucleus to the cytosol through NPC had not been explored so far [ 75 , 76 ] ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

Lu¹,

Nanayakkara²,

Sun³

et al. 2021

Redox Biology

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To determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).

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“…CASP1, a member of the caspase family, serves a critical role in the execution process of cell apoptosis ( Kapplusch et al, 2019 ). The expression of CASP1 was regulated, and the inflammasome activated by CASP1-NLRP3 dependent pathway can subsequently secrete IL-1β and IL-18, thus leading to dysfunctional autophagy ( Wang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Immunogenic cell death-led discovery of COVID-19 biomarkers and inflammatory infiltrates

Zhuo

Wang

et al. 2023

Front. Microbiol.

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Immunogenic cell death (ICD) serves a critical role in regulating cell death adequate to activate an adaptive immune response, and it is associated with various inflammation-related diseases. However, the specific role of ICD-related genes in COVID-19 remains unclear. We acquired COVID-19-related information from the GEO database and a total of 14 ICD-related differentially expressed genes (DEGs) were identified. These ICD-related DEGs were closely associated with inflammation and immune activity. Afterward, CASP1, CD4, and EIF2AK3 among the 14 DEGs were selected as feature genes based on LASSO, Random Forest, and SVM-RFE algorithms, which had reliable diagnostic abilities. Moreover, functional enrichment analysis indicated that these feature genes may have a potential role in COVID-19 by being involved in the regulation of immune response and metabolism. Further CIBERSORT analysis demonstrated that the variations in the immune microenvironment of COVID-19 patients may be correlated with CASP1, CD4, and EIF2AK3. Additionally, 33 drugs targeting 3 feature genes had been identified, and the ceRNA network demonstrated a complicated regulative association based on these feature genes. Our work identified that CASP1, CD4, and EIF2AK3 were diagnostic genes of COVID-19 and correlated with immune activity. This study presents a reliable diagnostic signature and offers an overview to investigate the mechanism of COVID-19.

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CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability

Cited by 11 publications

References 32 publications

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation

Immunogenic cell death-led discovery of COVID-19 biomarkers and inflammatory infiltrates

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