Mol Cell Proteomics. 2017 Jan 13. pii: mcp.M116.063602. doi: 10.1074/mcp.M116.063602. [Epub ahead of print]
Yang Z1,
Hou Y1,
Hao T1,
Rho HS2,
Wan J2,
Luan Y1,
Gao X1,
Yao J1,
Pan A1,
Xie Z1,
Qian J2,
Liao W1,
Zhu H2,
Zhou X3.
Abstract
Toxoplasma kinase ROP18 is a key molecule responsible for the virulence of Toxoplasma gondii; however, the mechanisms by which ROP18 exerts parasite virulence via interaction with host proteins remain limited to a small number of identified substrates. To identify a broader array of ROP18 substrates we successfully purified bioactive mature ROP18 and used it to probe a human proteome array. Sixty-eight new putative host targets were identified. Functional annotation analysis suggested that these proteins have a variety of functions including metabolic process, kinase activity and phosphorylation, cell growth, apoptosis and cell death, and immunity, indicating a pleiotropic role of ROP18 kinase. Among these proteins, four candidates, p53, p38, UBE2N, and Smad1 were further validated. We demonstrated that ROP18 targets p53, p38, UBE2N, and Smad1 for degradation. Importantly, we demonstrated that ROP18 phosphorylates Smad1 Ser187 to trigger its proteasome-dependent degradation. Further functional characterization of the substrates of ROP18 may enhance understanding of the pathogenesis of Toxoplasma infection and providing new therapeutic targets. Similar strategies could be used to identify novel host targets for other microbial kinases functioning at the pathogen-host interface.
Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
KEYWORDS:
Kinases*; Microbiology; Pathogens; Protein array; Protein-Protein Interactions*; host-pathogen interaction; proteome array
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