Canonical inflammasomes are innate immune signaling platforms that are formed in response to intracellular pathogen-associated signals and trigger caspase-1-dependent pyroptosis. Inflammasome formation and signaling is thought to mainly occur in myeloid cells, and in particular monocytes and macrophages. Here we show that small molecule inhibitors of dipeptidyl peptidases 8 and 9 (DPP8/9), which activate the related CARD8 and NLRP1 inflammasomes, also activate pyroptosis in human and rodent resting lymphocytes. We found that both CD4 + and CD8 + T cells were particularly sensitive to these inhibitors, although the sensitivity of T cells, like macrophages, varied considerably between species. In human T cells, we show that CARD8 mediates DPP8/9 inhibitor-induced pyroptosis. Intriguingly, although activated human T cells express the key proteins known to be required for CARD8-mediated pyroptosis, these cells were completely resistant to DPP8/9 inhibitors. Overall, these data show that resting lymphoid cells can activate at least one inflammasome, revealing additional cell types and states poised to undergo rapid pyroptotic cell death in response to danger-associated signals. NLRP1 and CARD8 are related human PRRs that form inflammasomes 6-9. NLRP1 and CARD8 have similar C-terminal ZU5, UPA, and CARD domains, but have different N-terminal regions (Fig. 1a). NLRP1 and CARD8 both undergo autoproteolysis at the C-terminal end of their ZU5 domains, generating N-and C-terminal fragments that remain non-covalently associated 10. Although the pathogen-associated signal (or signals) that activates NLRP1 and CARD8 has not been identified, small molecule inhibitors of the host serine proteases DPP8 and DPP9 (DPP8/9), including the nonselective DPP inhibitor Val-boroPro (VbP), were recently discovered to activate both NLRP1 and CARD8 6,9,11-13. DPP8/9 inhibitors induce the proteasome-mediated destruction of the NLRP1 and CARD8 N-terminal fragments through an unknown mechanism 6,14 , releasing their C-terminal fragments from autoinhibition. The liberated NLRP1 UPA-CARD indirectly recruits and activates pro-caspase-1 via ASC, whereas the CARD8 UPA-CARD directly recruits and activates pro-caspase-1 3. In addition, DPP8/9 binds directly to NLRP1 and CARD8. DPP8/9 inhibitors disrupt
Coronavirus Disease 2019 (COVID-19) has been the most severe public health challenge in this century. Two years after its emergence, the rapid development and deployment of effective COVID-19 vaccines have successfully controlled this pandemic and greatly reduced the risk of severe illness and death associated with COVID-19. However, due to its ability to rapidly evolve, the SARS-CoV-2 virus may never be eradicated, and there are many important new topics to work on if we need to live with this virus for a long time. To this end, we hope to provide essential knowledge for researchers who work on the improvement of future COVID-19 vaccines. In this review, we provided an up-to-date summary for current COVID-19 vaccines, discussed the biological basis and clinical impact of SARS-CoV-2 variants and subvariants, and analyzed the effectiveness of various vaccine booster regimens against different SARS-CoV-2 strains. Additionally, we reviewed potential mechanisms of vaccine-induced severe adverse events, summarized current studies regarding immune correlates of protection, and finally, discussed the development of next-generation vaccines.
The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.
The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin’s biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.
Purpose Inflammasomes are multiprotein complexes that detect danger-associated signals and trigger an immunostimulatory form of cell death called pyroptosis. NLRP1 is an innate immune receptor that assembles into an inflammasome, but the primary cell types in which NLRP1 is functional have not yet been fully established. Mutations in NLRP1 are associated with diseases of barrier epithelial tissues, including skin lesions and corneal intraepithelial dyskeratosis, suggesting that NLRP1 functions within the eye. Here, we investigated the expression and activity of the NLRP1 inflammasome in primary human corneal epithelial (pHCE) cells. Methods The small molecule Val-boroPro (VbP) activates the NLRP1 inflammasome. Proteasome (bortezomib, MG132) and caspase-1 (VX-765, Z-VAD-FMK) inhibitors block NLRP1 activation and downstream pyroptosis, respectively. Here, we treated pHCE cells with VbP alone or in combination proteasome inhibitors and caspase-1 inhibitors. We assessed NLRP1 expression and hallmarks of pyroptosis, including lytic cell rupture, cytokine processing and release, and gasdermin D (GSDMD) processing. Results VbP triggered pyroptosis in pHCE cells, as determined by cytokine secretion, GSDMD processing, and lactate dehydrogenase (LDH) release. Proteasome and caspase-1 inhibitors completely blocked this pyroptotic cell death. In contrast, other primary ocular epithelial cells did not undergo NLRP1-dependent pyroptosis. Conclusions Our findings demonstrate that NLRP1 forms a functional inflammasome in pHCE cells. Importantly, these data reveal that NLRP1 is a key innate immune sensor of the corneal epithelium, and moreover indicate how aberrant inflammasome activation causes corneal damage. Blockade of NLRP1 signaling may benefit patients with hyperactive NLRP1 mutations and warrants further investigation.
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