Abstract
SummaryTrypanosome parasites control their virulence and spread by using quorum sensing (QS) to generate transmissible “stumpy forms” in their host bloodstream. However, the QS signal “stumpy induction factor” (SIF) and its reception mechanism are unknown. Although trypanosomes lack G protein-coupled receptor signaling, we have identified a surface GPR89-family protein that regulates stumpy formation. TbGPR89 is expressed on bloodstream “slender form” trypanosomes, which receive the SIF signal, and when ectopically expressed, TbGPR89 drives stumpy formation in a SIF-pathway-dependent process. Structural modeling of TbGPR89 predicts unexpected similarity to oligopeptide transporters (POT), and when expressed in bacteria, TbGPR89 transports oligopeptides. Conversely, expression of an E. coli POT in trypanosomes drives parasite differentiation, and oligopeptides promote stumpy formation in vitro. Furthermore, the expression of secreted trypanosome oligopeptidases generates a paracrine signal that accelerates stumpy formation in vivo. Peptidase-generated oligopeptide QS signals being received through TbGPR89 provides a mechanism for both trypanosome SIF production and reception.
Highlights
G protein-coupled receptors (GPCRs) and other multipasstransmembrane proteins allow eukaryotic cells to perceive an enormous diversity of extracellular signals, enabling their response to environmental information
African trypanosomes lack conventional oligopeptide transporters, but we show that TbGPR89 can transport oligopeptides, which promote stumpy formation in vitro
In T. brucei Lister 427 90:13 monomorphic cells (Wirtz et al, 1999), which have lost the capacity for stumpy formation through serial passage, the protein was effectively expressed but there was only a subtle effect on cell growth (Figure 1D)
Summary
G protein-coupled receptors (GPCRs) and other multipasstransmembrane proteins allow eukaryotic cells to perceive an enormous diversity of extracellular signals, enabling their response to environmental information. Trypanosoma brucei spp., causing human and animal trypanosomiasis, live extracellularly in the bloodstream of their mammalian host and exploit environmental information to regulate their virulence and transmissibility. Morphologically ‘‘slender form’’ bloodstream trypanosomes proliferate until signaled to undergo development to non-proliferative ‘‘stumpy forms’’ adapted for transmission (MacGregor et al, 2012). This is a quorum-sensing (QS) type response triggered by the accumulation of a ‘‘stumpy induction factor’’ (SIF), the nature and mechanism of signaling remains unknown (Reuner et al, 1997; Vassella et al, 1997). Molecules at the cell surface that detect or transport SIF, or act at early steps in the signaling pathway, remain completely unknown, as is the SIF signal that drives QS
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