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COPs and POPs: Modulators of Inflammasome Activity¹

Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

Inflammasomes represent molecular platforms for the activation of inflammatory caspases and are essential for processing and secretion of the inflammatory cytokines IL-1β and IL-18. Multiple key proteins of inflammasomes contain caspase recruitment domains (CARDs) or pyrin domains (PYDs). Dissecting CARD- and PYD-mediated interactions substantially improved our understanding of the mechanisms by which these protein platforms are activated and emphasized their essential role during the inflammatory cytokine response. However, their precise regulation is still poorly understood. A family of small proteins that are composed of either a CARD or a PYD only emerged as important inflammasome regulators. These CARD-only proteins (COPs) and PYD-only proteins (POPs) function as endogenous dominant negative proteins that modulate the activity of inflammasomes in response to pathogen infection and tissue destruction. In this review we will summarize the most recent advances in the regulation of inflammasomes and highlight their importance for immunity and inflammatory disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants 1R01GM071723, R03AI067806, and R21AI067680, a grant from the Concern Foundation, and the Gallagher Family Research Endowment (to C.S.).

² Address correspondence and reprint requests to Dr. Christian Stehlik, Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 East Huron Street, Chicago, IL 60611. E-mail address: c-stehlik{at}northwestern.edu

³ Abbreviations used in this paper: PRR, pattern recognition receptor; CARD, caspase recruitment domain; COP, CARD-only protein; DAMP, damage-associated molecular pattern; FMF, familial Mediterranean fever; LRR, leucine-rich region; MDP, muramyl dipeptide; NLR, Nod-like receptor; NLRC, NLR containing a CARD; POP, PYD-only protein; PYD, pyrin domain; RA, rheumatoid arthritis.