Research: Subversion of mammalian signaling by parasite pseudokinases

We previously identified the ROP5 family as a set of highly polymorphic secreted effectors that are the greatest contributors to strain-specific differences in virulence. The ROP5 proteins are closely-related catalytically inactive protein kinases, or “pseudokinases,” that are encoded by a multi-copy locus. We determined that not only are polymorphisms in the ROP5 locus responsible for variation in virulence, but that ROP5 is absolutely essential for Toxoplasma to cause disease in mice. How can a dead enzyme affect disease outcome?

Pseudokinases are emerging as key regulators of cellular signaling, and especially within the mammalian immune system. Intriguingly, Toxoplasma has at least 60 predicted pseudokinases (>30% of its kinome, vs. 48 human pseudokinases – 9% of the human kinome), the majority of which are secreted into the host cytoplasm. Many of these pseudokinases are among Toxoplasma's most polymorphic genes, suggesting that they play an important role in pathogenesis via interactions with the host immune system. Thus, these proteins provide a platform for both the study of host-pathogen competition, and the evolution of pseudokinases as important regulators of cellular signaling.