title: Ubiquitylation of the initiator caspase DREDD is required for innate immune signalling.
abstract: Caspases have been extensively studied as critical initiators and executioners of cell death pathways. However, caspases also take part in non-apoptotic signalling events such as the regulation of innate immunity and activation of nuclear factor-κB (NF-κB). How caspases are activated under these conditions and process a selective set of substrates to allow NF-κB signalling without killing the cell remains largely unknown. Here, we show that stimulation of the Drosophila pattern recognition protein PGRP-LCx induces DIAP2-dependent polyubiquitylation of the initiator caspase DREDD. Signal-dependent ubiquitylation of DREDD is required for full processing of IMD, NF-κB/Relish and expression of antimicrobial peptide genes in response to infection with Gram-negative bacteria. Our results identify a mechanism that positively controls NF-κB signalling via ubiquitin-mediated activation of DREDD. The direct involvement of ubiquitylation in caspase activation represents a novel mechanism for non-apoptotic caspase-mediated signalling.
authors.affiliation: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
authors.forename: Annika
authors.initials: A
authors.lastname: Meinander
authors.forename: Christopher
authors.initials: C
authors.lastname: Runchel
authors.forename: Tencho
authors.initials: T
authors.lastname: Tenev
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Chan-Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Ribeiro
authors.forename: Meike
authors.initials: M
authors.lastname: Broemer
authors.forename: Francois
authors.initials: F
authors.lastname: Leulier
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Neal
authors.initials: N
authors.lastname: Silverman
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D029721:Drosophila Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006090:Gram-Negative Bacteria / Q000276:immunology*; D007113:Immunity, Innate; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C101626:Rel protein, Drosophila; D014157:Transcription Factors; C439909:imd protein, Drosophila; C118897:peptidoglycan recognition protein; D020169:Caspases; C431887:dredd protein, Drosophila