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Trypanosoma cruzi trans‐sialidase induces STAT3 and ERK activation by prokineticin receptor 2 binding
Author(s) -
Lattanzi Roberta,
Maftei Daniela,
Fullone Maria Rosaria,
Miele Rossella
Publication year - 2021
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.3586
Subject(s) - biology , trypanosoma cruzi , receptor , mapk/erk pathway , microbiology and biotechnology , mutant , signal transduction , genetics , gene , parasite hosting , world wide web , computer science
Abstract Tc85, as other members of trans‐sialidase family, is involved in Trypanosoma cruzi parasite adhesion to mammalian cells. Particularly, Tc85 acts through specific interactions with prokineticin receptor 2, a G‐protein coupled receptor involved in diverse physiological and pathological processes. In this manuscript, through biochemical analyses, we demonstrated that LamG, a Tc85 domain, physically interacts with the prokineticin receptor 2. Moreover, expressing prokineticin receptor 1 and 2 we demonstrated that LamG specifically activates prokineticin receptor 2 through a strong coupling with G αi or G αq proteins in yeast strains and inducing ERK and NFAT phosphorylation in CHO mammalian cells. To demonstrate a Tc85 physiological role in T . cruzi infection of the nervous system, we evidenced a strong STAT3 and ERK activation by LamG in mice Dorsal Root Ganglia. L173R is the most common prokineticin receptor 2 mutation reported in Kallmann syndrome and it is a founder mutation. Our results demonstrated that in cells co‐expressing prokineticin receptor 2 mutant (L173R) and wild‐type, LamG is unable to induce signal transduction. The L173R mutation in heterozygosity may allow for a selective advantage due to increased protection from T . cruzi infection. Significance of the study The Chagas' disease affecting millions of people worldwide is caused by an eukaryotic microorganism called T . cruzi . Pharmacological treatment for patients with Chagas' disease is still limited. Indeed, the small number of drugs available shows important side effects that can be debilitating for patient health. In order to replicate and produce new parasites T . cruzi uses a complex of different proteins produced by both the parasite and the human host cells. So, understanding the molecular details used by T . cruzi to be internalised by different types of human cells is an important step towards the development of new drugs for this disease. Prokineticin receptors are relevant for host‐parasite interaction. To characterise the signal transduction cascade induced by their activation may help to understand the molecular details of cell infection, leading to novel therapeutic alternative for this debilitating disease.