The tetrapeptide sequence of IL-18 and IL-1β regulates their recruitment and activation by inflammatory caspases.

Inflammasomes are multiprotein signaling complexes that activate the innate immune system. Canonical inflammasomes recruit and activate caspase-1, which then cleaves and activates IL-1β and IL-18, as well as gasdermin D (GSDMD) to induce pyroptosis. In contrast, non-canonical inflammasomes, caspases-4/-5 (CASP4/5) in humans and caspase-11 (CASP11) in mice, are known to cleave GSDMD, but their role in direct processing of other substrates besides GSDMD has remained unknown.

The tetrapeptide sequence of IL-1β regulates its recruitment and activation by inflammatory caspases.

The mammalian innate immune system uses germline-encoded cytosolic pattern-recognition receptors (PRRs) to detect intracellular danger signals. At least six of these PRRs are known to form multiprotein complexes called inflammasomes which activate cysteine proteases known as caspases. Canonical inflammasomes recruit and activate caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines such as IL-1β and IL-18, as well as the pore forming protein, gasdermin D (GSDMD), to induce pyroptotic cell death.

Phosphatidylinositol 3-phosphate and Hsp70 protect from heat-induced cell death.

Phosphatidylinositol 3-phosphate (PI(3)P) levels in correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the stress response was unknown. Here, we used PI3K inhibitors and antimalarial agents to examine the importance of PI(3)P under thermal conditions recapitulating malarial fever.

chaperonin TRiC/CCT identified as a target of the antihistamine clemastine using parallel chemoproteomic strategy.

The antihistamine clemastine inhibits multiple stages of the parasite that causes malaria, but the molecular targets responsible for its parasite inhibition were unknown. Here, we applied parallel chemoproteomic platforms to discover the mechanism of action of clemastine and identify that clemastine binds to the TCP-1 ring complex or chaperonin containing TCP-1 (TRiC/CCT), an essential heterooligomeric complex required for de novo cytoskeletal protein folding. Clemastine destabilized all eight TRiC subunits based on thermal proteome profiling (TPP).

RNA-Seq Analysis Illuminates the Early Stages of Liver Infection.

The apicomplexan parasites spp. are the causative agents of malaria, a disease that poses a significant global health burden. spp.