Abstract
Explorations of the functions of receptors of the TNF/NGF family have led to the discovery of various signaling proteins, many of which were later found to mediate effects of other inducers as well. We now have quite detailed knowledge of the mechanisms and molecular complexes by which some of the signaling proteins mediate these additional effects. This, however, is not the case for caspase-8. This signaling protein, which was initially identified as the proximal enzyme in the induction of apoptotic death by the death receptors, was subsequently reported to serve additional functions independently of those receptors. Whereas the mechanisms by which caspase-8 mediates cell death induction have been described in detail, almost nothing is known of the way it serves other functions. Findings that we presented at the 12th Biennial TNF Conference indicate that one of the physiological roles of this enzyme is to suppress inflammation. We further showed that one way by which caspase-8 does this is by associating with the RIG-I signaling complex and inhibiting some of the signaling mechanisms that are triggered upon formation of this complex in response to cytoplasmic ribonucleic acid. We illustrated the physiological role of caspase-8 in suppressing excessive inflammation by describing a fatal chronic skin inflammatory disease that occurs in mice as a result of deletion of caspase-8 from the epidermis.
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Rothe M, Wong SC, Henzel WJ, Goeddel DV (1994) A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 78:681–692
Brakebusch C, Nophar Y, Kemper O, Engelmann H, Wallach D (1992) Cytoplasmic truncation of the p55 tumour necrosis factor (TNF) receptor abolishes signalling, but not induced shedding of the receptor. Embo J 11:943–950
Itoh N, Nagata S (1993) A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 268:10932–10937
Tartaglia LA, Ayres TM, Wong GH, Goeddel DV (1993) A novel domain within the 55 kd TNF receptor signals cell death. Cell 74:845–853
Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D (1995) A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270:7795–7798
Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512
Chung JY, Park YC, Ye H, Wu H (2002) All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 115:679–688
Zapata JM, Martinez-Garcia V, Lefebvre S (2007) Phylogeny of the TRAF/MATH domain. Adv Exp Med Biol 597:1–24
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666
Ben Moshe T, Kang TB, Kovalenko A, Barash H, Abramovitch R, Galun E, Wallach D (2008) Cell-autonomous and non-cell-autonomous functions of caspase-8. Cytokine Growth Factor Rev 19:209–217
Kovalenko A, Kim JC, Kang TB, Rajput A, Bogdanov K, Dittrich-Breiholz O, Kracht M, Brenner O, Wallach D (2009) Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J Exp Med 206:2161–2177
Kang TB, Oh G-S, Scandella E, Bolinger B, Ludewig B, Kovalenko A, Wallach D (2008) Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J Immunol 181:2522–2532
Ben Moshe T, Barash H, Kang TB, Kim JC, Kovalenko A, Gross E, Schuchmann M, Abramovitch R, Galun E, Wallach D (2007) Role of caspase-8 in hepatocyte response to infection and injury in mice. Hepatology 45:1014–1024
Pasparakis M, Courtois G, Hafner M, Schmidt-Supprian M, Nenci A, Toksoy A, Krampert M, Goebeler M, Gillitzer R, Israel A, Krieg T, Rajewsky K, Haase I (2002) TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417:861–866
Stratis A, Pasparakis M, Rupec RA, Markur D, Hartmann K, Scharffetter-Kochanek K, Peters T, van Rooijen N, Krieg T, Haase I (2006) Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation. J Clin Invest 116:2094–2104
Okabe Y, Kawane K, Nagata S (2008) IFN regulatory factor (IRF) 3/7- dependent and -independent gene induction by mammalian DNA that escapes degradation. Eur J Immunol 38:3150–3158
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Rajput, A. et al. (2011). Anti-inflammatory Functions of Caspase-8. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_25
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DOI: https://doi.org/10.1007/978-1-4419-6612-4_25
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