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Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia

Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-try...

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Detalles Bibliográficos
Autores principales: Le, Quang T., Lyons, Jonathan J., Naranjo, Andrea N., Olivera, Ana, Lazarus, Robert A., Metcalfe, Dean D., Milner, Joshua D., Schwartz, Lawrence B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780998/
https://www.ncbi.nlm.nih.gov/pubmed/31337736
http://dx.doi.org/10.1084/jem.20190701
Descripción
Sumario:Both α-tryptase and β-tryptase are preferentially expressed by human mast cells, but the purpose of α-tryptase is enigmatic, because its tetramers lack protease activity, whereas β-tryptase tetramers are active proteases. The monogenic disorder called hereditary α-tryptasemia, due to increased α-tryptase gene copies and protein expression, presents with clinical features such as vibratory urticaria and dysautonomia. We show that heterotetramers composed of 2α- and 2β-tryptase protomers (α/β-tryptase) form naturally in individuals who express α-tryptase. α/β-Tryptase, but not homotetramer, activates protease-activated receptor-2 (PAR2), which is expressed on cell types such as smooth muscle, neurons, and endothelium. Also, only α/β-tryptase makes mast cells susceptible to vibration-triggered degranulation by cleaving the α subunit of the EGF-like module–containing mucin-like hormone receptor-like 2 (EMR2) mechanosensory receptor. Allosteric effects of α-tryptase protomers on neighboring β-tryptase protomers likely result in the novel substrate repertoire of α/β-tryptase tetramers that in turn cause some of the clinical features of hereditary α-tryptasemia and of other disorders involving mast cells.