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OP0024 The Function of PSTPIP1 and S100A8/S100A9 in Hyperzincaemia & Hypercalprotectinaemia and the PAPA-Syndrom
  1. S. Fassl1,
  2. D. Holzinger1,
  3. J. Austermann1,
  4. T. Vogl1,
  5. J. Roth1
  1. 1Unversity Hospital Muenster, Institute of Immunology, Muenster, Germany., Münster, Germany


Background Hypercalprotectinaemia and hyperzincaemia is a very rare autoinflammatory syndrome that is characterized by excessively high S100A8/S100A9 complex (calprotectin) serum concentrations (0.9-12.0 g/l, normal range < 0.001 g/l) not present in any other inflammatory condition. S100A8 and S100A9 are phagocyte-derived Damage Associated Molecular Pattern (DAMP) proteins. They can be released by tubulin-dependent alternative secretory pathways to induce pro-inflammatory effects through interaction with Toll-like receptor 4 (TLR-4) dependent signalling pathways (1, 2). By analyzing seven hypercalprotecinaemia patients we could identify a novel autosomal dominant mutation in the proline serine threonine phosphatase-interacting protein 1 (PSTPIP1) gene. Six of the seven patients were heterozygous carrier of an E250K substitution encoded by exon 11 of the PSTPIP1 gene. Other PSTPIP1 mutations are responsible for the classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (3) which presents with elevated, albeit significantly lower S100A8/S100A9 levels compared to patients with E250K mutation.

Objectives The molecular link between PSTPIP1 mutations and elevated S100A8/S100A9 concentrations is currently unknown. The present project focuses therefore on the identification of molecular links between PSTPIP1 and S100A8/S100A9 and the potential function of PSTPIP1 for the release of S100A8/S100A9.

Methods The intracellular distribution of E250K and wildtype PSTPIP1 was determined in transfected cell lines by immunofluorescence analysis. The interactions between PSTPIP1, S100A8/S100A9 and microtubules were characterized via immunoprecipitations. These interaction studies were confirmed and further characterized by in vitro interaction studies using a modified S100A8/S100A9-ELISA and microtubule binding assays.

Results The immunofluorescence and immunoprecipitation results point towards an interaction between PSTPIP1 and S100A8/S100A9 in vivo. Moreover we could specify this interaction in vitro as direct and strictly calcium-dependent. Using several deletion constructs of PSTPIP1 we have some first evidences indicating that the S100A8/S100A9 binding motif is located within the same region described to be mutated in hyperzincaemia and hypercalprotectinaemia patients. Microtubule co-sedimentation experiments indicate a mutual interference of PSTPIP1 and S100A8/S100A9 on their interaction with microtubules which is altered by using the E250K mutated PSTPIP1.

Conclusions PSTPIP1 and S100A8/S100A9 directly interact in a calcium-dependent manner and the E250K mutation is apparently located within the S100A8/S100A9 binding region. Therefore this mutation might have an influence on the S100A8/S100A9-PSTPIP1 interaction. In addition PSTPIP1 and S100A8/S100A9 seem to have a regulatory function on their tubulin binding capability. This in turn might be of important relevance for the tubulin-dependent secretion of the S100A8/S100A9 proteins and putatively the cause for the high serum concentrations of S100A8/S100A9 in hyperzincaemia and hypercalprotectinaemia patients.


  1. Vogl et al. (2007) Nat. Med. 13, 1042-1049;

  2. Rammes et al. (1997) J. Biol. Chem. 272, 9496-9502;

  3. Wise et al. (2002) Hum. Mol. Gen. 11(8), 961-969.

Disclosure of Interest None Declared

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