Caspase-1: is IL-1 just the tip of the ICEberg?

Abstract

Caspase-1, formerly known as interleukin (IL)-1-converting enzyme is best established as the protease responsible for the processing of the key pro-inflammatory cytokine IL-1β from an inactive precursor to an active, secreted molecule. Thus, caspase-1 is regarded as a key mediator of inflammatory processes, and has become synonymous with inflammation. In addition to the processing of IL-1β, caspase-1 also executes a rapid programme of cell death, termed pyroptosis, in macrophages in response to intracellular bacteria. Pyroptosis is also regarded as a host response to remove the niche of the bacteria and to hasten their demise. These processes are generally accepted as the main roles of caspase-1. However, there is also a wealth of literature supporting a direct role for caspase-1 in non-infectious cell death processes. This is true in mammals, but also in non-mammalian vertebrates where caspase-1-dependent processing of IL-1β is absent because of the lack of appropriate caspase-1 cleavage sites. This literature is most prevalent in the brain where caspase-1 may directly regulate neuronal cell death in response to diverse insults. We attempt here to summarise the evidence for caspase-1 as a cell death enzyme and propose that, in addition to the processing of IL-1β, caspase-1 has an important and a conserved role as a cell death protease.

Figure 1

Is IL-1 just the tip of the ICEberg? Caspase-1 has a broad range of substrate specificity that extends far beyond inflammation. Depicted here is an iceberg of caspase-1 substrates in which IL-1- and inflammation-related protein substrates are situated at the tip of the iceberg. The uppercase ICE in ICEberg relates to the former name for caspase-1, ICE. Also shown are some selected substrates that may contribute to the phenotype of a pyroptotic cell death. In addition to inflammation, substrates related to the ontologies of cell death, cytoskeleton and metabolism are shown. The full list of substrates is provided as Supplementary information (Supplementary Table 1)

Figure 2

Conservation of caspase-1-dependent cell death and IL-1β processing. The development of caspase-1 as an inflammatory, in addition to a cell death protease occurred in mammals. Highlighted here are conserved caspase-1 cleavage sites in mammalian vertebrate pro-IL-1β that are not observed in non-mammalian pro-IL-1β sequences. The schematic diagram shows the link between caspase-1, cell death, and inflammation in mammals, and that the link is not present between caspase-1 and inflammation in non-mammalian vertebrates. DANGER represents any source of stress that could drive an inflammatory response such as tissue injury, disease, or infection

Figure 3

Inflammatory and apoptotic caspase cross talk. Shown is a summary of some of the interactions between inflammatory and apoptotic caspases. In particular, parallels and overlap between the formation of the inflammasome and the apoptosome are shown. Bold arrows are established links. The dashed arrows highlight possible interactions as suggested by the reviewed literature