title: Poly-ADP-ribosylation-mediated degradation of ARTD1 by the NLRP3 inflammasome is a prerequisite for osteoclast maturation.
abstract: Evidence implicates ARTD1 in cell differentiation, but its role in skeletal metabolism remains unknown. Osteoclasts (OC), the bone-resorbing cells, differentiate from macrophages under the influence of macrophage colony-stimulating factor (M-CSF) and receptor-activator of NF-κB ligand (RANKL). We found that M-CSF induced ADP-ribosyltransferase diphtheria toxin-like 1 (ARTD1) auto-ADP-ribosylation in macrophages, a modification that marked ARTD1 for cleavage, and subsequently, for degradation upon RANKL exposure. We established that ARTD1 proteolysis was NLRP3 inflammasome-dependent, and occurred via the proteasome pathway. Since ARTD1 is cleaved at aspartate(214), we studied the impact of ARTD1 rendered uncleavable by D214N substitution (ARTD1(D214N)) on skeletal homeostasis. ARTD1(D214N), unlike wild-type ARTD1, was resistant to cleavage and degradation during osteoclastogenesis. As a result, ARTD1(D214N) altered histone modification and promoted the abundance of the repressors of osteoclastogenesis by interfering with the expression of B lymphocyte-induced maturation protein 1 (Blimp1), the master regulator of anti-osteoclastogenic transcription factors. Importantly, ARTD1(D214N)-expressing mice exhibited higher bone mass compared with controls, owing to decreased osteoclastogenesis while bone formation was unaffected. Thus, unless it is degraded, ARTD1 represses OC development through transcriptional regulation.
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: C
authors.initials: C
authors.lastname: Qu
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Alippe
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Bonar
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: R
authors.initials: R
authors.lastname: Civitelli
authors.affiliation: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Abu-Amer
authors.affiliation: Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
authors.forename: M O
authors.initials: MO
authors.lastname: Hottiger
authors.affiliation: Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mbalaviele
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D059748:Proteolysis; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; D006657:Histones; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases