title: Tartrate-Resistant Acid Phosphatase Deficiency in the Predisposition to Systemic Lupus Erythematosus.
abstract: Mutations in the ACP5 gene, which encodes tartrate-resistant acid phosphatase (TRAP), cause the immuno-osseous disorder spondyloenchondrodysplasia, which includes as disease features systemic lupus erythematosus (SLE) and a type I interferon (IFN) signature. Our aims were to identify TRAP substrates, determine the consequences of TRAP deficiency in immune cells, and assess whether ACP5 mutations are enriched in sporadic cases of SLE.
  
  
  
  Interaction between TRAP and its binding partners was tested by a yeast 2-hybrid screening, confocal microscopy, and immunoprecipitation/Western blotting. TRAP knockdown was performed using small interfering RNA. Phosphorylation of osteopontin (OPN) was analyzed by mass spectrometry. Nucleotide sequence analysis of ACP5 was performed by Sanger sequencing or next-generation sequencing.
  
  
  
  TRAP and OPN colocalized and interacted in human macrophages and plasmacytoid dendritic cells (PDCs). TRAP dephosphorylated 3 serine residues on specific OPN peptides. TRAP knockdown resulted in increased OPN phosphorylation and increased nuclear translocation of IRF7 and P65, with resultant heightened expression of IFN-stimulated genes and IL6 and TNF following Toll-like receptor 9 stimulation. An excess of heterozygous ACP5 missense variants was observed in SLE compared to controls (P = 0.04), and transfection experiments revealed a significant reduction in TRAP activity in a number of variants.
  
  
  
  Our findings indicate that TRAP and OPN colocalize and that OPN is a substrate for TRAP in human immune cells. TRAP deficiency in PDCs leads to increased IFNα production, providing at least a partial explanation for how ACP5 mutations cause lupus in the context of spondyloenchondrodysplasia. Detection of ACP5 missense variants in a lupus cohort suggests that impaired TRAP functioning may increase susceptibility to sporadic lupus.
authors.affiliation: University of Washington, Seattle.
authors.forename: Jie
authors.initials: J
authors.lastname: An
authors.affiliation: University of Manchester and St. Mary's Hospital, Central Manchester Foundation Trust, Manchester, UK.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Briggs
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Audrey
authors.initials: A
authors.lastname: Dumax-Vorzet
authors.affiliation: Universidad de Granada-Junta de Andalucía, Granada, Spain, and Oklahoma Medical Research Foundation, Oklahoma City.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Pediatric Rheumatology Unit, Femme Mère Enfant Hospital, Hospices Civils de Lyon, INSERM U1111, University of Lyon, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belot
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Beresford
authors.affiliation: University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Bruce
authors.affiliation: Universidade do Porto, Abel Salazar Institute of Biomedical Sciences, Porto, Portugal.
authors.forename: Claudia
authors.initials: C
authors.lastname: Carvalho
authors.affiliation: INSERM U823/UJF/EFS, UGA, INSERM U1209, CNRS 5309, Immunobiology and Immunotherapy of Cancers and Chronic Diseases, Grenoble, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Chaperot
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Frostegård
authors.affiliation: INSERM U823/UJF/EFS, UGA, INSERM U1209, CNRS 5309, Immunobiology and Immunotherapy of Cancers and Chronic Diseases, Grenoble, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Plumas
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
authors.affiliation: King's College London, Guy's Hospital, London, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: University of Washington, Seattle.
authors.forename: Alice
authors.initials: A
authors.lastname: Wiedeman
authors.affiliation: University of Manchester, Manchester, UK, and Institut Imagine, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: University of Washington, Seattle.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000209:etiology*; D008264:Macrophages; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics; D053495:Osteopontin / Q000378:metabolism; D010766:Phosphorylation; D000071681:Tartrate-Resistant Acid Phosphatase / Q000172:deficiency* / Q000235:genetics
chemical_list: D053495:Osteopontin; C000605510:ACP5 protein, human; D000071681:Tartrate-Resistant Acid Phosphatase