Oligopeptide signaling through TbGPR89 drives trypanosome quorum sensing

Federico Rojas; Eleanor Silvester; Julie Young; Rachel Milne; Mabel Tettey; Douglas R. Houston; Malcolm D. Walkinshaw; Irene Pérez-Pi; Manfred Auer; Helen Denton; Terry K. Smith; Joanne Thompson; Keith R. Matthews

doi:10.1016/j.cell.2018.10.041

Oligopeptide signaling through TbGPR89 drives trypanosome quorum sensing

Federico Rojas, Eleanor Silvester, Julie Young, Rachel Milne, Mabel Tettey, Douglas R. Houston, Malcolm D. Walkinshaw, Irene Pérez-Pi, Manfred Auer, Helen Denton, Terry K. Smith, Joanne Thompson, Keith R. Matthews

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	e16
Pages (from-to)	306-317
Number of pages	12
Journal	Cell
Volume	176
Issue number	1-2
Early online date	29 Nov 2018
DOIs	https://doi.org/10.1016/j.cell.2018.10.041
Publication status	Published - 10 Jan 2019

Keywords

Parasite
Quorum sensing
Stumpy induction factor
Differentiation
GPR89
Oligopeptide
Sleeping sickness
Trypanosome brucei

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2018.10.041Licence: CC BY

Royas-2018-Oligopeptide-signalling-Cell-CC
Copyright 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 5.42 MBLicence: CC BY

lipid catabolism: Investigating the typanosomatid lysosome and its role in lipid catabolism.
Smith, T. K. (PI)
Medical Research Council
1/06/15 → 31/01/19
Project: Standard

Terry K Smith
- tks1st-andrews.acuk
- School of Biology - Director of Biomedical Sciences Research Complex, Professor
- Sir James Mackenzie Institute for Early Diagnosis
- Biomedical Sciences Research Complex
Person: Academic

Cite this

@article{c9069efb361e4a93aeab903e665e5bc0,

title = "Oligopeptide signaling through TbGPR89 drives trypanosome quorum sensing",

abstract = "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.",

keywords = "Parasite, Quorum sensing, Stumpy induction factor, Differentiation, GPR89, Oligopeptide, Sleeping sickness, Trypanosome brucei",

author = "Federico Rojas and Eleanor Silvester and Julie Young and Rachel Milne and Mabel Tettey and Houston, {Douglas R.} and Walkinshaw, {Malcolm D.} and Irene P{\'e}rez-Pi and Manfred Auer and Helen Denton and Smith, {Terry K.} and Joanne Thompson and Matthews, {Keith R.}",

note = "K.R.M. is funded by a Wellcome Trust Investigator Award (103740/Z14/Z) and a Royal Society Wolfson Research merit award (WM140045). The Medical Research Council (MR/M020118/1) supported T.K.S., and the Wellcome Trust supported J.T. (202094/Z/16/Z). M.A. received financial support from the Scottish Universities Life Sciences Alliance (SULSA; https://www.sulsa.ac.uk) and a Medical Research Council strategic grant (J54359).",

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month = jan,

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doi = "10.1016/j.cell.2018.10.041",

language = "English",

volume = "176",

pages = "306--317",

journal = "Cell",

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T1 - Oligopeptide signaling through TbGPR89 drives trypanosome quorum sensing

AU - Rojas, Federico

AU - Silvester, Eleanor

AU - Young, Julie

AU - Milne, Rachel

AU - Tettey, Mabel

AU - Houston, Douglas R.

AU - Walkinshaw, Malcolm D.

AU - Pérez-Pi, Irene

AU - Auer, Manfred

AU - Denton, Helen

AU - Smith, Terry K.

AU - Thompson, Joanne

AU - Matthews, Keith R.

N1 - K.R.M. is funded by a Wellcome Trust Investigator Award (103740/Z14/Z) and a Royal Society Wolfson Research merit award (WM140045). The Medical Research Council (MR/M020118/1) supported T.K.S., and the Wellcome Trust supported J.T. (202094/Z/16/Z). M.A. received financial support from the Scottish Universities Life Sciences Alliance (SULSA; https://www.sulsa.ac.uk) and a Medical Research Council strategic grant (J54359).

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 - Parasite

KW - Quorum sensing

KW - Stumpy induction factor

KW - Differentiation

KW - GPR89

KW - Oligopeptide

KW - Sleeping sickness

KW - Trypanosome brucei

U2 - 10.1016/j.cell.2018.10.041

DO - 10.1016/j.cell.2018.10.041

M3 - Article

SN - 0092-8674

VL - 176

SP - 306

EP - 317

JO - Cell

JF - Cell

IS - 1-2

M1 - e16

ER -

Oligopeptide signaling through TbGPR89 drives trypanosome quorum sensing

Abstract

Keywords

UN SDGs

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Projects

lipid catabolism: Investigating the typanosomatid lysosome and its role in lipid catabolism.

Profiles

Terry K Smith

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