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

Jie An, Tracy Briggs, Audrey Dumax-Vorzet, Marta E Alarcón-Riquelme, Alexandre Belot, Michael Beresford, Ian Bruce, Claudia Carvalho , Laurence Chaperot, Johan Frostegård, Joel Plumas, Gillian Rice, Timothy J Vyse, Alice Wiedeman, Yanick Crow, Keith B. Elkon

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Objectives: Mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRAP), cause the immuno-osseous disorder Spondyloenchondrodysplasia, that includes systemic lupus erythematosus (SLE) and a type I interferon signature as disease features. 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 SLE.
Methods: Interaction between TRAP and binding partners was tested by a yeast-2-hybrid screen, confocal microscopy and by immunoprecipitation/western blot analysis. TRAP knockdown was performed by siRNA and phosphorylation of osteopontin (OPN) by mass spectrometry. Nucleotide sequence analysis of ACP5 was performed by Sanger or Next GEN sequencing.
Results: TRAP and OPN co-localized and interacted in human macrophages and plasmacytoid dendritic cells (pDCs). TRAP dephosphorylated three 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 interferon-stimulated genes, IL-6 and TNF following TLR9 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.
Conclusions: Our findings indicate that TRAP and OPN co-localize and that OPN is a substrate for TRAP in human immune cells. TRAP deficiency in pDCs leads to increased interferon-alpha 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 function may increase susceptibility to sporadic lupus. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)131-142
JournalArthritis and Rheumatology
Issue number1
Early online date7 Jul 2016
Publication statusPublished - 2017


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