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Proteolysis of serum amyloid A and AA amyloid proteins by cysteine proteases: cathepsin B generates AA amyloid proteins and cathepsin L may prevent their formation

C Röcken¹, R Menard², F Bühling³, S Vöckler¹, J Raynes⁴, B Stix¹, S Krüger¹, A Roessner¹, T Kähne⁵

¹ Institute of Pathology, Otto-von-Guericke-University of Magdeburg, Germany
² Biotechnology Research Institute, NRCC, Montreal, Canada
³ Institute of Immunology, Otto-von-Guericke-University of Magdeburg, Germany
⁴ Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
⁵ Institute of Experimental Internal Medicine, Otto-von-Guericke-University of Magdeburg, Germany

Correspondence to:
Correspondence to:
Dr C Röcken
Institute of Pathology, Otto-von-Guericke-University, Leipziger Str 44, D-39120 Magdeburg, Germany; christoph.roecken{at}medizin.uni-magdeburg.de

Background: AA amyloidosis develops in patients with chronic inflammatory diseases. The AA amyloid proteins are proteolytic fragments obtained from serum amyloid A (SAA). Previous studies have provided evidence that endosomes or lysosomes might be involved in the processing of SAA, and contribute to the pathology of AA amyloidosis.

Objective: To investigate the anatomical distribution of cathepsin (Cath) B and CathL in AA amyloidosis and their ability to process SAA and AA amyloid proteins.

Methods and results: CathB and CathL were found immunohistochemically in every patient with AA amyloidosis and displayed a spatial relationship with amyloid in all the cases studied. Both degraded SAA and AA amyloid proteins in vitro. With the help of mass spectrometry 27 fragments were identified after incubation of SAA with CathB, nine of which resembled AA amyloid proteins, and seven fragments after incubation with CathL. CathL did not generate AA amyloid-like peptides. When native human AA amyloid proteins were used as a substrate 26 fragments were identified after incubation with CathB and 18 after incubation with CathL.

Conclusion: The two most abundant and ubiquitously expressed lysosomal proteases can cleave SAA and AA amyloid proteins. CathB generates nine AA amyloid-like proteins by its carboxypeptidase activity, whereas CathL may prevent the formation of AA amyloid proteins by endoproteolytic activity within the N-terminal region of SAA. This is particularly interesting, because AA amyloidosis is a systemic disease affecting many organs and tissue types, almost all of which express CathB and CathL.

Abbreviations: Cath, cathepsin; HS, heparan sulphate; MALDI-TOF-MS, matrix assisted laser desorption/ionisation time of flight mass spectrometer; MMPs, matrix metalloproteinases; rSAA, recombinant serum amyloid A; SAA, serum amyloid A

Keywords: amyloid; cathepsin; rheumatoid arthritis

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