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Active Caspase-1-Mediated Secretion of Retinoic Acid Inducible Gene-I¹

Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea

Caspase-1 is an inflammatory caspase that controls the activation and secretion of the inflammatory cytokines, IL-1β and IL-18. We observed that cellular levels of retinoic acid-inducible gene-I (RIG-I) were enhanced when the pan-caspase inhibitor Z-VAD-fmk or caspase-1-specific inhibitor Z-WEHD-fmk blocked caspase activity. Overexpression of caspase-1 reduced cellular levels of RIG-I and inhibited RIG-I-mediated signaling activity. Enzymatic activity of caspase-1 was necessary to control RIG-I, although it was not a substrate of proteolytic cleavage by caspase-1. Caspase-1 physically interacted with full length RIG-I, but not with mutant forms lacking either the amino- or carboxyl-terminal domains. RIG-I was present in the supernatant of cells transfected with active caspase-1 but not with caspase-4. Stimulating cells with LPS and ATP also induced secretion of endogenous RIG-I in macrophages. Our data suggest a novel mechanism that negatively regulates RIG-I-mediated signaling activity via caspase-1-dependent secretion of RIG-I protein.

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 grants from the MOST/KOSEF to the National Core Research Center for Systems Bio-Dynamics (R15-2004-033), the Korea Healthcare Technology R&D Project (A080084), and the Core Research Fund of POSTECH.

² Address correspondence and reprint requests to Joo-Yeon Yoo, 208 Life Science Bldg. Department of Life Sciences, POSTECH, Pohang, Republic of Korea. E-mail address: jyoo{at}postech.ac.kr

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular patterns; CARD, carboxyl-terminal caspase recruitment domain; DAMP, danger-associated molecular patterns; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LDH, lactate dehydrogenase; NLR, nucleotide-binding and oligomerization domain-like receptors; RD, repressor domain; RIG-I, retinoic acid-inducible gene-I.