title: The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors.
abstract: The innate immune system needs to distinguish between harmful and innocuous stimuli to adapt its activation to the level of threat. How Drosophila mounts differential immune responses to dead and live Gram-negative bacteria using the single peptidoglycan receptor PGRP-LC is unknown. Here we describe rPGRP-LC, an alternative splice variant of PGRP-LC that selectively dampens immune response activation in response to dead bacteria. rPGRP-LC-deficient flies cannot resolve immune activation after Gram-negative infection and die prematurely. The alternative exon in the encoding gene, here called rPGRP-LC, encodes an adaptor module that targets rPGRP-LC to membrane microdomains and interacts with the negative regulator Pirk and the ubiquitin ligase DIAP2. We find that rPGRP-LC-mediated resolution of an efficient immune response requires degradation of activating and regulatory receptors via endosomal ESCRT sorting. We propose that rPGRP-LC selectively responds to peptidoglycans from dead bacteria to tailor the immune response to the level of threat.
authors.affiliation: Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland.
authors.forename: Claudine
authors.initials: C
authors.lastname: Neyen
authors.affiliation: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Runchel
authors.affiliation: Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland.
authors.forename: Fanny
authors.initials: F
authors.lastname: Schüpfer
authors.affiliation: The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
authors.affiliation: Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland.
authors.forename: Bruno
authors.identifier: 0000-0001-7970-1667
authors.initials: B
authors.lastname: Lemaitre
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D055786:Gene Knockout Techniques; D016905:Gram-Negative Bacterial Infections / Q000276:immunology*; D007109:Immunity / Q000235:genetics; D056747:Immunomodulation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism*; D016973:Pectobacterium carotovorum / Q000276:immunology*; D011485:Protein Binding; D021382:Protein Sorting Signals / Q000235:genetics; D059748:Proteolysis; D059368:RNA Isoforms / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; C111892:DIAP2 protein, Drosophila; C054756:DptA protein, Drosophila; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D051034:Inhibitor of Apoptosis Proteins; C532213:Pirk protein, Drosophila; D021382:Protein Sorting Signals; D059368:RNA Isoforms; C118897:peptidoglycan recognition protein