RT Journal Article
SR Electronic
T1 A rapidly evolving polybasic motif modulates bacterial detection by guanylate binding proteins
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 689554
DO 10.1101/689554
A1 Kristin M. Kohler
A1 Miriam Kutsch
A1 Anthony S. Piro
A1 Graham Wallace
A1 Jörn Coers
A1 Matthew F. Barber
YR 2019
UL http://biorxiv.org/content/early/2019/07/02/689554.abstract
AB Cell-autonomous immunity relies on the rapid detection of invasive pathogens by host proteins. Guanylate binding proteins (GBPs) have emerged as key mediators of vertebrate immune defense through their ability to recognize a diverse array of intracellular pathogens and pathogen-containing cellular compartments. Human and mouse GBPs have been shown to target distinct groups of microbes, although the molecular determinants of pathogen specificity remain unclear. We show that rapid diversification of a C-terminal polybasic motif (PBM) in primate GBPs controls recognition of the model cytosolic bacterial pathogen Shigella flexneri. By swapping this membrane-binding motif between primate GBP orthologs, we find that the ability to target S. flexneri has been enhanced and lost in specific lineages of New World monkeys. Single substitutions in rapidly evolving sites of the GBP1 PBM are sufficient to abolish or restore bacterial detection abilities, illustrating a role for epistasis in the evolution of pathogen recognition. We further demonstrate that the squirrel monkey GBP2 C-terminal domain recently gained the ability to target S. flexneri through a stepwise process of convergent evolution. These findings reveal a mechanism by which accelerated evolution of a PBM shifts GBP target specificity and aid in resolving the molecular basis of GBP function in cell-autonomous immune defense.