Final published version
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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Oligopeptide Signaling through TbGPR89 Drives Trypanosome Quorum Sensing.
AU - Rojas Martinez, Federico
AU - Silvester, Eleanor
AU - Young, Julie
AU - Milne, Rachel
AU - Tettey, Mabel Deladem
AU - Houston, Douglas R.
AU - Walkinshaw, Malcolm D.
AU - Perez-Pi, Irene
AU - Auer, Manfred
AU - Denton, Helen
AU - Smith, Terry K
AU - Thompson, Joanne
AU - Matthews, Keith R.
PY - 2019/1/10
Y1 - 2019/1/10
N2 - Trypanosome 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.
AB - Trypanosome 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.
KW - Trypanosome brucei
KW - parasite
KW - quorum sensing
KW - stumpy induction factor
KW - differentiation
KW - GPR89
KW - oligopeptide
KW - sleeping sickness
U2 - 10.1016/j.cell.2018.10.041
DO - 10.1016/j.cell.2018.10.041
M3 - Journal article
C2 - 30503212
VL - 176
SP - 306-317.e16
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1-2
ER -