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The Drosophila Inhibitor of Apoptosis (IAP) DIAP2 Is Dispensable for Cell Survival, Required for the Innate Immune Response to Gram-negative Bacterial Infection, and Can Be Negatively Regulated by the Reaper/Hid/Grim Family of IAP-binding Apoptosis Inducers

Huh, Jun R. and Foe, Ian and Muro, Israel and Chen, Chun Hong and Seol, Jae Hong and Yoo, Soon Ji and Guo, Ming and Park, Jin Mo and Hay, Bruce A. (2007) The Drosophila Inhibitor of Apoptosis (IAP) DIAP2 Is Dispensable for Cell Survival, Required for the Innate Immune Response to Gram-negative Bacterial Infection, and Can Be Negatively Regulated by the Reaper/Hid/Grim Family of IAP-binding Apoptosis Inducers. Journal of Biological Chemistry, 282 (3). pp. 2056-2068. ISSN 0021-9258. doi:10.1074/jbc.M608051200. https://resolver.caltech.edu/CaltechAUTHORS:HUHjbc07

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Abstract

Many inhibitor of apoptosis (IAP) family proteins inhibit apoptosis. IAPs contain N-terminal baculovirus IAP repeat domains and a C-terminal RING ubiquitin ligase domain. Drosophila IAP DIAP1 is essential for the survival of many cells, protecting them from apoptosis by inhibiting active caspases. Apoptosis initiates when proteins such as Reaper, Hid, and Grim bind a surface groove in DIAP1 baculovirus IAP repeat domains via an N-terminal IAP-binding motif. This evolutionarily conserved interaction disrupts DIAP1-caspase interactions, unleashing apoptosis-inducing caspase activity. A second Drosophila IAP, DIAP2, also binds Rpr and Hid and inhibits apoptosis in multiple contexts when overexpressed. However, due to a lack of mutants, little is known about the normal functions of DIAP2. We report the generation of diap2 null mutants. These flies are viable and show no defects in developmental or stress-induced apoptosis. Instead, DIAP2 is required for the innate immune response to Gram-negative bacterial infection. DIAP2 promotes cytoplasmic cleavage and nuclear translocation of the NF-{kappa}B homolog Relish, and this requires the DIAP2 RING domain. Increasing the genetic dose of diap2 results in an increased immune response, whereas expression of Rpr or Hid results in down-regulation of DIAP2 protein levels. Together these observations suggest that DIAP2 can regulate immune signaling in a dose-dependent manner, and this can be regulated by IBM-containing proteins. Therefore, diap2 may identify a point of convergence between apoptosis and immune signaling pathways.


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https://doi.org/10.1074/jbc.M608051200DOIArticle
Additional Information:© 2007 the American Society for Biochemistry and Molecular Biology. Received for publication, August 22, 2006 Published, JBC Papers in Press, October 26, 2006, DOI 10.1074/jbc.M608051200. We thank Drs. Loren Miller and Todd Ciche for providing us with S. aureus and E. cloacae bacterial strains; Jules Hoffmann, Bruno Lemaitre, Makoto Nakamura, Kathryn Anderson, Ronald Davis, and Carl Thummel for fly stocks; Lark Kyun Kim, Young Joon Kim, Svenja Stöven, and Dan Hultmark for antibodies; Nieng Yan, Yigong Shi, and Carl Thummel for plasmids; Rainbow Transgenic Flies for generating fly transformants; Kelvin Nguyen for help during the early stages of this work; and Eric Davidson for use of the real time PCR machine. 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. The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.
Issue or Number:3
DOI:10.1074/jbc.M608051200
Record Number:CaltechAUTHORS:HUHjbc07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:HUHjbc07
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7328
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:31 Jan 2007
Last Modified:08 Nov 2021 20:41

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