Caspase-Mediated Cleavage, IAP Binding, and Ubiquitination: Linking Three Mechanisms Crucial for Drosophila NF-κB Signaling
Department of Medicine, Division of Infectious Diseases and Immunology
Immunity, Innate; Drosophila; Intracellular Signaling Peptides and Proteins; Signal Transduction; DNA Cleavage; Caspases; Inhibitor of Apoptosis Proteins; Ubiquitination
Innate immune responses are critical for the immediate protection against microbial infection. In Drosophila, infection leads to the rapid and robust production of antimicrobial peptides through two NF-κB signaling pathways—IMD and Toll. The IMD pathway is triggered by DAP-type peptidoglycan, common to most Gram-negative bacteria. Signaling downstream from the peptidoglycan receptors is thought to involve K63 ubiquitination and caspase-mediated cleavage, but the molecular mechanisms remain obscure. We now show that PGN stimulation causes caspase-mediated cleavage of the imd protein, exposing a highly conserved IAP-binding motif (IBM) at its neo-N terminus. A functional IBM is required for the association of cleaved IMD with the ubiquitin E3-ligase DIAP2. Through its association with DIAP2, IMD is rapidly conjugated with K63-linked polyubiquitin chains. These results mechanistically connect caspase-mediated cleavage and K63 ubiquitination in immune-induced NF-κB signaling.
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Citation: Nicholas Paquette, Meike Broemer, Kamna Aggarwal, Li Chen, Marie Husson, Deniz Erturk-Hasdemir, Jean-Marc Reichhart, Pascal Meier, Neal Silverman. Caspase-Mediated Cleavage, IAP Binding, and Ubiquitination: Linking Three Mechanisms Crucial for Drosophila NF-[kappa]B Signaling. Molecular Cell, Volume 37, Issue 2, 29 January 2010, Pages 172-182. Link to article on publisher's website
Paquette, Nicholas Paul; Broemer, Meike; Aggarwal, Kamna; Chen, Li; Husson, Marie; Erturk Hasdemir, Deniz; Reichhart, Jean-Marc; Meier, Pascal; and Silverman, Neal S., "Caspase-Mediated Cleavage, IAP Binding, and Ubiquitination: Linking Three Mechanisms Crucial for Drosophila NF-κB Signaling" (2010). Infectious Diseases and Immunology Publications and Presentations. Paper 41.