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Now showing items 1 - 3 of 3

  • Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2

    Mares, Alina   Miah, Afjal H.   Smith, Ian E. D.   Rackham, Mark   Thawani, Aditya R.   Cryan, Jenni   Haile, Pamela A.   Votta, Bartholomew J.   Beal, Allison M.   Capriotti, Carol   Reilly, Michael A.   Fisher, Don T.   Zinn, Nico   Bantscheff, Marcus   MacDonald, Thomas T.   Vossenkamper, Anna   Dace, Phoebe   Churcher, Ian   Benowitz, Andrew B.   Watt, Gillian   Denyer, Jane   Scott-Stevens, Paul   Harling, John D.  

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  • Caspase-8 Collaborates with Caspase-11 to Drive Tissue Damage and Execution of Endotoxic Shock

    Manda, Pratyusha   Feng, Yanjun   Lyons, John D.   Berger, Scott B.   Otani, Shunsuke   DeLaney, Alexandra   Tharp, Gregory K.   Maner-Smith, Kristal   Burd, Eileen M.   Schaeffer, Michelle   Hoffman, Sandra   Capriotti, Carol   Roback, Linda   Young, Cedrick B.   Liang, Zhe   Ortlund, Eric A.   DiPaolo, Nelson C.   Bosinger, Steven   Bertin, John   Gough, Peter J.   Brodsky, Igor E.   Coopersmith, Craig M.   Shayakhmetov, Dmitry M.   Mocarski, Edward S.  

    The execution of shock following high dose E. coli lipopolysaccharide (LPS) or bacterial sepsis in mice required pro-apoptotic caspase-8 in addition to pro-pyroptotic caspase-11 and gasdermin D. Hematopoietic cells produced MyD88- and TRIF-dependent inflammatory cytokines sufficient to initiate shock without any contribution from cas pase-8 or caspase-11. Both proteases had to be present to support tumor necrosis factor- and interferon-beta-dependent tissue injury first observed in the small intestine and later in spleen and thymus. Caspase-11 enhanced the activation of caspase-8 and extrinsic cell death machinery within the lower small intestine. Neither caspase-8 nor caspase-11 was individually sufficient for shock. Both caspases collaborated to amplify inflammatory signals associated with tissue damage. Therefore, combined pyroptotic and apoptotic signaling mediated endotoxemia independently of RIPK1 kinase activity and RIPK3 function. These observations bring to light the relevance of tissue compartmentalization to disease processes in vivo where cytokines act in parallel to execute diverse cell death pathways.
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  • Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice.

    Berger, Scott B   Kasparcova, Viera   Hoffman, Sandy   Swift, Barb   Dare, Lauren   Schaeffer, Michelle   Capriotti, Carol   Cook, Michael   Finger, Joshua   Hughes-Earle, Angela   Harris, Philip A   Kaiser, William J   Mocarski, Edward S   Bertin, John   Gough, Peter J  

    RIP1 (RIPK1) kinase is a key regulator of TNF-induced NF-kappaB activation, apoptosis, and necroptosis through its kinase and scaffolding activities. Dissecting the balance of RIP1 kinase activity and scaffolding function in vivo during development and TNF-dependent inflammation has been hampered by the perinatal lethality of RIP1-deficient mice. In this study, we generated RIP1 kinase-dead (Ripk1(K45A)) mice and showed they are viable and healthy, indicating that the kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1(K45A) mice were specifically protected against necroptotic stimuli in vitro and in vivo, we crossed them with SHARPIN-deficient cpdm mice, which develop severe skin and multiorgan inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1(K45A) mice with the cpdm strain protected against all cpdm-related pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases. Copyright =C2=A9 2014 by The American Association of Immunologists, Inc.
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