Fig. 3: Schematic representation of CatB and its substrates in the core pyroptosis machinery.
From: Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways
Activation of NLRP3 inflammasome in macrophages requires two steps: priming and activation. The priming step is provided by inflammatory stimuli such as TLR agonists, which induce NF-κB-mediated NLRP3 and pro-IL-1β expression. The activation step is triggered by PAMPs and DAMPs. Upon stimulation, NLRP3 oligomerizes and recruits ASC through homotypic PYD-PYD interactions and leads to helical ASC filament formation. Assembled ASC recruits caspase 1 and enables proximity-induced caspase 1 self-cleavage and activation, which in turn cleaves pro-IL-1β and GSDMD. GSDMD inserts into the membrane, forming pores and inducing pyroptosis. It has been demonstrated that CatB is a critical factor for NLRP3 inflammasome activation but the precise molecular mechanisms and cellular space are unclear. The remained questions regarding CatB are listed at the right-bottom of the figure. CatB cathepsin B, DAMPs damage-associated molecular patterns, GSDMD gasdermin, IL interleukin, IκB I kappa B kinase, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3 NACHT-, leucine-rich-repeat- (LRR), and pyrin domain (PYD)-containing protein 3, PAMPS pathogen-associated molecular patterns, ROS reactive oxygen species, TLR toll-like receptor.
