Caspases in Cell Death, Inflammation, and Disease

Abstract

Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational insight into the molecular mechanisms that control caspase activation has emerged in recent years. Important advancements include the identification of additional inflammasome platforms and pathways that regulate activation of inflammatory caspases; the discovery of gasdermin D as the effector of pyroptosis and interleukin (IL)-1 and IL-18 secretion; and the existence of substantial crosstalk between inflammatory and apoptotic initiator caspases. A better understanding of the mechanisms regulating caspase activation has supported initial efforts to modulate dysfunctional cell death and inflammation pathways in a suite of communicable, inflammatory, malignant, metabolic, and neurodegenerative diseases. Here, we review current understanding of caspase biology with a prime focus on the inflammatory caspases and outline important topics for future experimentation.

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…1,2 Active caspases induce regulated cell death, apoptosis, and pyroptosis, by cleaving distinct substrates; caspases proteolytically activate specific cell death mediators, process the same and/or other caspases to transduce and amplify cell death signals, and cleave cytoskeletal components to facilitate cell morphological changes. [3][4][5] Thus, the form of death induced in cells by a caspase is influenced by substrate specificity and the availability of downstream signaling molecules of the caspase. The majority of caspases participate in the induction of apoptosis.…”

“…The majority of caspases participate in the induction of apoptosis. 1,3 Caspase-8 and caspase-9 are activated in death receptor-mediated (also known as extrinsic) and intrinsic apoptosis pathways, respectively. These caspases, in turn, serve as initiator caspases that directly or indirectly activate downstream effector caspases, such as caspase-3 and caspase-7.…”

“…7,8,12,13 Caspase-4, -5, and -11 serve as sensors of cytosolic LPS. 3,14,15 These caspases directly bind with LPS, resulting in the activation of these caspases via dimerization-induced autoproteolysis, which, in turn, leads to pyroptosis. 16 Caspase-4, -5, and -11 do not process pro-IL-1β and pro-IL-18 directly, but trigger the formation of the NLRP3 inflammasome by inducing the efflux of K + , leading to the caspase-1-mediated maturation of IL-1β and IL-18.…”

“…16 Caspase-4, -5, and -11 do not process pro-IL-1β and pro-IL-18 directly, but trigger the formation of the NLRP3 inflammasome by inducing the efflux of K + , leading to the caspase-1-mediated maturation of IL-1β and IL-18. 3,[17][18][19] The inflammasome formed by this mode is called the noncanonical inflammasome. LPS gains access to caspase-4, -5, and -11 during the entry of Gram-negative bacteria PYD or CARD.…”

“…Pyroptotic cells rapidly lose cell membrane integrity, increase in size, and have smaller nuclei. 3 DNA damage also occurs upon pyroptosis, and pyroptotic cells become positive in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling with a lower intensity than apoptotic cells. The initial event in pyroptosis is caspase-1-dependent pore formation in the plasma membrane, which causes water influx, cell swelling, and ultimately cell lysis.…”