Caspase regulation in inflammation.

Abstract

Caspases, or cysteine-dependent aspartate specific proteases, comprise a family of cysteine proteases that cleave after an aspartic acid residue. They have been implicated in two aspects of cellular signaling: proteolytic activation of specific interleukins and programmed cell death. Caspases are produced as single chain zymogens that possess a low protease activity. Caspase zymogens normally lie dormant in healthy cells and consist of a variable length caspase activation domain (CARD) followed by two subunits that comprise the catalytic domain. When a cell receives either a death stimulus or a signal to generate IL-1beta, a caspase cascade is initiated. To initiate this cascade, the stimulus must cause oligomerization of an adaptor molecule that in turn recruits multiple initiator caspase zymogens into close proximity with one another causing autocatalyic processing and subsequent activation. The only exception is caspase-9, a proapoptotic initiator caspase activated without autocatalytic processing. Activation of the initiator caspase is a critical step in determining cell fate and, as such, it is important to understand how it occurs and how it is regulated. Caspase-1 is the protease responsible for the proteolytic conversion of the inactive IL-1beta cytokine to its mature proinflammatory cytokine. IL-1beta is perhaps the most potent of endogenous pyrogens. We show that caspase-1 is activated via recruitment to its upstream adaptor Nod2 in response to an inflammatory stimulus. Furthermore, we demonstrate how Nod2 mutations found in Crohn's disease, a member of the inflammatory bowel disorders, lead to increased IL-1beta release, diagnostic for this disease. Endogenous inhibition of IL-1beta release is accomplished by ICEBERG, a novel CARD only decoy adaptor that binds caspase-1 and inhibits its activation and the consequent release of IL-1beta. While studying the homotypic interaction motifs that form the molecular glue that bind the signaling machinery responsible for caspase activation, we discovered a novel interaction motif called the pyrin domain (PYD). PYD is structurally related to the CARD, the death domain (DD), and the death effector domain (DED), all members of the 'death domain fold' superfamily. The DD, DED, CARD and PYD modules are found almost exclusively in proteins involved in apoptosis or inflammation.