RT Journal Article
SR Electronic
T1 An unusual and vital protein with guanylate cyclase and P4-ATPase domains in a pathogenic protist
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900402
DO 10.26508/lsa.201900402
VO 2
IS 3
A1 Özlem Günay-Esiyok
A1 Ulrike Scheib
A1 Matthias Noll
A1 Nishith Gupta
YR 2019
UL https://www.life-science-alliance.org/content/2/3/e201900402.abstract
AB cGMP signaling is one of the master regulators of diverse functions in eukaryotes; however, its architecture and functioning in protozoans remain poorly understood. Herein, we report an exclusive guanylate cyclase coupled with N-terminal P4-ATPase in a common parasitic protist, Toxoplasma gondii. This bulky protein (477-kD), termed TgATPaseP-GC to fairly reflect its envisaged multifunctionality, localizes in the plasma membrane at the apical pole of the parasite, whereas the corresponding cGMP-dependent protein kinase (TgPKG) is distributed in the cytomembranes. TgATPaseP-GC is refractory to genetic deletion, and its CRISPR/Cas9–assisted disruption aborts the lytic cycle of T. gondii. Besides, Cre/loxP–mediated knockdown of TgATPaseP-GC reduced the synthesis of cGMP and inhibited the parasite growth due to impairments in the motility-dependent egress and invasion events. Equally, repression of TgPKG by a similar strategy recapitulated phenotypes of the TgATPaseP-GC–depleted mutant. Notably, despite a temporally restricted function, TgATPaseP-GC is expressed constitutively throughout the lytic cycle, entailing a post-translational regulation of cGMP signaling. Not least, the occurrence of TgATPaseP-GC orthologs in several other alveolates implies a divergent functional repurposing of cGMP signaling in protozoans, and offers an excellent drug target against the parasitic protists.