The trypsin-like protease Der p 3, a major allergen of the house dust mite Dermatophagoides pteronyssinus, is synthesized as a zymogen, termed proDer p 3. No recombinant source of Der p 3 has been described yet, and the zymogen maturation mechanism remains to be elucidated. The Der p 3 zymogen was produced in Pichia pastoris. We demonstrated that the recombinant zymogen is glycosylated at the level of its propeptide. We showed that the activation mechanism of proDer p 3 is intermolecular and is mediated by the house dust mite cysteine protease Der p 1. The primary structure of the proDer p 3 propeptide is associated with a unique zymogen activation mechanism, which is different from those described for the trypsin-like family and relies on the house dust mite papain-like protease Der p 1. This is the first report of a recombinant source of Der p 3, with the same enzymatic activity as the natural enzyme and trypsin. Glycosylation of the propeptide was found to decrease the rate of maturation. Finally, we showed that recombinant Der p 3 is inhibited by the free modified prosequence T P1 R. House dust mite (HDM)6 allergens have been shown to be causative factors of allergic manifestations such as atopic dermatitis, perennial rhinitis, or bronchial asthma. More than 80% of patients suffering from allergic asthma are positive for mite extracts and have large amounts of IgE specific for mite allergens. In Europe, the most prevalent species of house dust mites are Dermatophagoides pteronyssinus and Dermatophagoides farinae, depending on relative humidity and temperature. No less than 23 groups of allergens were identified from extracts of these species (1, 2).Although the group 1 and 2 allergens were extensively studied, those from group 3 were poorly characterized. In D. pteronyssinus, the allergen of this group has been first identified by Stewart et al. (3) as a trypsin-like protease termed Der p 3. The binding of IgE from sera of allergic patients to Der f 3, a D. farinae protease homologous to Der p 3, appears to depend on the purity of the allergen, the tested patient populations, and the sensitivity of the technique (4). Although the frequency of IgE reactivity measured toward Der p 3 was ϳ70 -80%, suggesting that Der p 3 is a major allergen (5), a recent study determined a lower allergenic potency similar to mite allergen groups 8 and 10 (6). On the basis of both sequence comparisons and enzymatic studies, Der p 3 has been classified among the trypsin-like proteases from the S1A serine proteases family. Two other serine proteases with chymotryptic and collagenolytic activities and showing 36 and 76% of identity with Der p 3, were also identified in D. pteronyssinus extracts and were termed Der p 6 and Der p 9, respectively (7-9).The trypsin-like protease Der p 3 displays 47% of identity with salmon trypsin and 45% with bovine trypsin (3, 10, 11). All
In more than 20% of the world population, sensitization to house dust mite allergens triggers typical allergic diseases such as allergic rhinitis and asthma. Amongst the 23 mite allergen groups hitherto identified, group 1 is cysteine proteases belonging to the papain-like family whereas groups 3, 6, and 9 are serine proteases displaying trypsin, chymotrypsin, and collagenolytic activities, respectively. While these proteases are more likely to be involved in the mite digestive system, they also play critical roles in the initiation and in the chronicity of the allergic response notably through the activation of innate immune pathways. All these allergenic proteases are expressed in mite as inactive precursor form. Until recently, the exact mechanisms of their maturation into active proteases remained to be fully elucidated. Recent breakthroughs in the understanding of the activation mechanisms of mite allergenic protease precursors have highlighted an uncommon and unique maturation pathway orchestrated by group 1 proteases that tightly regulates the proteolytic activities of groups 1, 3, 6, and 9 through complex intra- or inter-molecular mechanisms. This review presents and discusses the currently available knowledge of the activation mechanisms of group 1, 3, 6, and 9 allergens of Dermatophagoides pteronyssinus laying special emphasis on their localization, regulation, and interconnection.
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