title: The Pallbearer E3 ligase promotes actin remodeling via RAC in efferocytosis by degrading the ribosomal protein S6.
abstract: Clearance of apoptotic cells (efferocytosis) is achieved through phagocytosis by professional or amateur phagocytes. It is critical for tissue homeostasis and remodeling in all animals. Failure in this process can contribute to the development of inflammatory autoimmune or neurodegenerative diseases. We found previously that the PALL-SCF E3-ubiquitin ligase complex promotes apoptotic cell clearance, but it remained unclear how it did so. Here we show that the F-box protein PALL interacts with phosphorylated ribosomal protein S6 (RpS6) to promote its ubiquitylation and proteasomal degradation. This leads to RAC2 GTPase upregulation and activation and F-actin remodeling that promotes efferocytosis. We further show that the specific role of PALL in efferocytosis is driven by its apoptotic cell-induced nuclear export. Finding a role for RpS6 in the negative regulation of efferocytosis provides the opportunity to develop new strategies to regulate this process.
authors.affiliation: Department of Immunology and Microbial Science and Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Immunology and Microbial Science and Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, London WC1E 6BT, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Silva
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: James
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Entomology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Guillou
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Entomology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Buchon
authors.affiliation: Department of Immunology and Microbial Science and Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Medical Research Council Laboratory for Molecular Cell Biology, London WC1E 6BT, UK. Electronic address: nfranc@scripps.edu.
authors.forename: Nathalie C
authors.initials: NC
authors.lastname: Franc
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified / Q000254:growth & development / Q000378:metabolism; D004331:Drosophila melanogaster / Q000254:growth & development / Q000378:metabolism*; D047468:Immunoprecipitation; D010587:Phagocytosis / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D038601:Ribosomal Protein S6; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D020744:rac GTP-Binding Proteins