CASP1

CASP1 Full Name

Caspase 1

CASP1 Introduction

Caspase-1 (interleukin-1β converting enzyme, ICE) is a cysteine-aspartic acid protease. The only established central biological function for CASP1 is as the final effector molecule of the inflammasome signaling pathway. In non-stimulated homeostatic cells, CASP1 is maintained as an inactive zymogen in the cytoplasm in the form of pro-caspase-1. Upon sensing of "danger signals" including infectious pathogens, tissue damage, and metabolic stress, intracellular pattern recognition receptors (e.g., NLRP3) oligomerize and recruit the adaptor protein ASC, and then subsequently recruit pro-caspase-1, leading to the assembly of a large multiprotein signaling platform known as the inflammasome. In the inflammasome complex, pro-caspase-1 then undergoes proximity-induced autocatalytic cleavage, which in turn produces a catalytically active heterotetramer. Active CASP1 then executes its most important biochemical function, by cleaving its two key substrates, the two critical pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18, into their mature and highly bioactive forms IL-1β and IL-18, respectively, which are then released to the extracellular space. Active CASP1 can also cleave Gasdermin D (GSDMD). The GSDMD N-terminal fragment forms membrane pores, which leads to the induction of a type of programmed cell death called pyroptosis, a highly pro-inflammatory form of cell lysis.

Figure 1. The priming process, triggering process, and executive effects of caspase-1. (Source: Ye X, et al. 2022)

Mutations in genes responsible for autoinflammatory diseases, such as cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS), lead to chronic and unregulated activation of the inflammasome (NLRP3, in particular), which in turn causes unrestrained CASP1 activation and IL-1β overproduction, resulting in the systemic inflammatory symptoms of periodic fever, rash and arthritis. In ALS, there is evidence of aberrant CASP1 activation in motor neurons and glial cells (notably microglia), and in SOD1 mutant mouse models of ALS, CASP1 activation has been directly linked to motor neuron death. In these models, genetic deletion or pharmacologic inhibition of CASP1 activity delays disease progression and extends lifespan, providing clear evidence that CASP1-dependent neuroinflammation and cell death is an important link in the ALS pathological cascade. Similarly, early evidence in PD suggests a role for CASP1 in α-synuclein-induced neuroinflammation. In addition, CASP1 activity has been implicated in neuroinflammation in other diseases, such as epilepsy, and is now being explored as a drug target for treating epilepsy.

Alternate Names for CASP1

CASP1; caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase); caspase 1, apoptosis related cysteine protease (interleukin 1, beta, convertase) , IL1BC; caspase-1; caspase 1; ICE; Caspase 1

• 1. Ye X, et al. Caspase-1: A Promising Target for Preserving Blood-Brain Barrier Integrity in Acute Stroke. Front Mol Neurosci. 2022 Mar 18;15:856372.
  2. Sollberger G, et al. Caspase-1: the inflammasome and beyond. Innate Immun. 2014 Feb;20(2):115-25.