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

Abstract

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.

When alpha meets beta, mast cells get hyper

“…Indeed, Lyons et al (2016) reported the contribution of α-tryptase gene copy number to serum α-tryptase levels and the severity of disease phenotype. These earlier findings from Lyons et al (2016) are consistent with the observations from the Le et al (2019) study, which showed that higher α/β-tryptase gene dosage correlates with higher tryptase activity. Moreover, the higher relative stability of α/β-tryptase compared with β-tryptase may account for the enhanced degranulation response observed in the Le et al study.…”

“…Vibration was used to trigger mast cell degranulation, as vibratory urticaria was reported to be a common symptom in patients with hereditary α-tryptasemia. Le et al (2019) also revealed the elements of time dependency and dose dependency in the mechanism of action of α/β-tryptase in modulating downstream inflammatory responses. Hence, their findings suggest that patients with relatively higher α-tryptase gene dosage could exhibit heightened mast cell responses and severity of resultant inflammatory/anaphylactic pathogenesis, particularly in tissues with a high abundance of resident mast cells as well as tryptaseresident cell types.…”

“…This naturally occurring α/β-tryptase was not on the list of previously reported gene products of human tryptase genes, but this unique protein type is present in macaques (Trivedi et al, 2007). Le et al (2019) investigated the clinical role and implications of α-tryptase in the context of individuals carrying an extra α-tryptase-encoding gene. Individuals with this extra α-tryptase-encoding gene are characterized by elevated α-tryptase mRNA and protryptase levels, which lead to α-tryptase-associated disorders such as hereditary α-tryptasemia.…”

“…Tryptases are also implicated in tumorigenesis, tumor invasion, and metastasis (Ammendola et al, 2014). Hence, the discovery of the catalytically active α/β-tryptase by Le et al (2019) may also serve as a potential target in cancer drug development.…”

Elevated Serum Tryptase in Non-Anaphylaxis Cases: A Concise Review

“…MCs from these patients do not appear to be more prone to degranulation, indicating the problem is not a disorder of MC activation [29]. A recent study found that in these patients, α-tryptase forms tetramers with β-tryptase in MCs and mediates the biological activity and hence symptoms of hereditary α-tryptasemia [30].…”