TY - JOUR
T1 - Divergent kinase regulates membrane ultrastructure of the Toxoplasma parasitophorous vacuole
AU - Beraki, Tsebaot
AU - Hu, Xiaoyu
AU - Broncel, Malgorzata
AU - Young, Joanna C.
AU - O'Shaughnessy, William J.
AU - Borek, Dominika
AU - Treeck, Moritz
AU - Reese, Michael L.
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019
Y1 - 2019
N2 - Apicomplexan parasites replicate within a protective organelle, called the parasitophorous vacuole (PV). The Toxoplasma gondii PV is filled with a network of tubulated membranes, which are thought to facilitate trafficking of effectors and nutrients. Despite being critical to parasite virulence, there is scant mechanistic understanding of the network's functions. Here, we identify the parasite-secreted kinase WNG1 (With-No-Gly-loop) as a critical regulator of tubular membrane biogenesis. WNG1 family members adopt an atypical protein kinase fold lacking the glycine rich ATPbinding loop that is required for catalysis in canonical kinases. Unexpectedly, we find that WNG1 is an active protein kinase that localizes to the PV lumen and phosphorylates PV-resident proteins, several ofwhich are essential for the formation of a functional intravacuolar network. Moreover, we show thatWNG1-dependent phosphorylation of these proteins is required for their membrane association, and thus their ability to tubulate membranes. Consequently, WNG1 knockout parasites have an aberrant PV membrane ultrastructure. Collectively, our results describe a unique family of Toxoplasma kinases and implicate phosphorylation of secreted proteins as a mechanism of regulating PV development during parasite infection.
AB - Apicomplexan parasites replicate within a protective organelle, called the parasitophorous vacuole (PV). The Toxoplasma gondii PV is filled with a network of tubulated membranes, which are thought to facilitate trafficking of effectors and nutrients. Despite being critical to parasite virulence, there is scant mechanistic understanding of the network's functions. Here, we identify the parasite-secreted kinase WNG1 (With-No-Gly-loop) as a critical regulator of tubular membrane biogenesis. WNG1 family members adopt an atypical protein kinase fold lacking the glycine rich ATPbinding loop that is required for catalysis in canonical kinases. Unexpectedly, we find that WNG1 is an active protein kinase that localizes to the PV lumen and phosphorylates PV-resident proteins, several ofwhich are essential for the formation of a functional intravacuolar network. Moreover, we show thatWNG1-dependent phosphorylation of these proteins is required for their membrane association, and thus their ability to tubulate membranes. Consequently, WNG1 knockout parasites have an aberrant PV membrane ultrastructure. Collectively, our results describe a unique family of Toxoplasma kinases and implicate phosphorylation of secreted proteins as a mechanism of regulating PV development during parasite infection.
KW - Chaperone
KW - Host-pathogen interaction
KW - Kinase
KW - Phosphorylation
KW - Pseudokinase
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U2 - 10.1073/pnas.1816161116
DO - 10.1073/pnas.1816161116
M3 - Article
C2 - 30850550
AN - SCOPUS:85063964285
SN - 0027-8424
VL - 116
SP - 6361
EP - 6370
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 13
ER -