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Arthritis Rheumatol. 2017 Jan;69(1):131-142. doi: 10.1002/art.39810. Epub 2016 Dec 2.

Tartrate-Resistant Acid Phosphatase Deficiency in the Predisposition to Systemic Lupus Erythematosus.

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University of Washington, Seattle.
University of Manchester and St. Mary's Hospital, Central Manchester Foundation Trust, Manchester, UK.
University of Manchester, Manchester, UK.
Universidad de Granada-Junta de Andalucía, Granada, Spain, and Oklahoma Medical Research Foundation, Oklahoma City.
Pediatric Rheumatology Unit, Femme Mère Enfant Hospital, Hospices Civils de Lyon, INSERM U1111, University of Lyon, Lyon, France.
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Universidade do Porto, Abel Salazar Institute of Biomedical Sciences, Porto, Portugal.
INSERM U823/UJF/EFS, UGA, INSERM U1209, CNRS 5309, Immunobiology and Immunotherapy of Cancers and Chronic Diseases, Grenoble, France.
Karolinska Institutet, Stockholm, Sweden.
King's College London, Guy's Hospital, London, UK.
University of Manchester, Manchester, UK, and Institut Imagine, Laboratory of Neurogenetics and Neuroinflammation, Paris, France.



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.

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