A quantitative interactome map reveals affinity tailored hijacking of human cellular functions by resident and pathogenic bacteria
Abstract
Bacteria employ molecular mimicry to hijack host cellular functions for their own benefit. Despite the wealth of data mapping human-bacteria interactions, a comprehensive view of how these networks are fine-tuned remains elusive. In particular, there have been no large-scale screenings measuring human-bacterial protein-protein binding affinities to explore their role in functional and pathological outcomes. Here, we report the largest quantitative interactome to date between the family of human PDZ domains and C-terminal PDZ-binding motifs (PBMs) in effectors from pathogenic and resident gut bacteria. We show that bacteria tailor effector sequences to bind PDZ domains with similar or higher binding affinities than human PBMs to hijack their associated cellular functions. For a subset of the dataset, we validate PDZ-PBM interactions with the corresponding full-length proteins and show that for pathogenic E. coli effector NleA, its C-terminal PBM is necessary for interactions with proteins involved in intracellular transport and membrane organization, probably impacting the host glycocalyx to favor infection. Finally, we show that motifs overlapping with effector PBMs target interaction modules other than PDZ domains, adding an additional layer of complexity to the host-microbe molecular dialogue.
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BibTeX
@misc{fernandezmacgregor2026quantitative,
title = {{A quantitative interactome map reveals affinity tailored hijacking of human cellular functions by resident and pathogenic bacteria}},
author = {Jaime Fernandez-Macgregor and Laura Ilari and Fabien Durbesson and Stéphane Audebert and Luc Camoin and Bastien Morlet and Virginie Millet and Jean Michel Dela Vedova-Costa and Charlene Gaedke and Vincent Kourilsky and Lou Bergogne and Eric Martinez and Achille Broggi and Jean-Paul Borg and Søren Østergaard and Gilles Trave and Elodie Monsellier and Christine Brun and Andreas Zanzoni and Renaud Vincentelli},
howpublished = {HAL},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.755967},
url = {https://amu.hal.science/hal-05796678v1},
note = {CC BY-NC 4.0},
}
RIS
TY - UNPB
TI - A quantitative interactome map reveals affinity tailored hijacking of human cellular functions by resident and pathogenic bacteria
AU - Jaime Fernandez-Macgregor
AU - Laura Ilari
AU - Fabien Durbesson
AU - Stéphane Audebert
AU - Luc Camoin
AU - Bastien Morlet
AU - Virginie Millet
AU - Jean Michel Dela Vedova-Costa
AU - Charlene Gaedke
AU - Vincent Kourilsky
AU - Lou Bergogne
AU - Eric Martinez
AU - Achille Broggi
AU - Jean-Paul Borg
AU - Søren Østergaard
AU - Gilles Trave
AU - Elodie Monsellier
AU - Christine Brun
AU - Andreas Zanzoni
AU - Renaud Vincentelli
PY - 2026
DA - 2026/10/02
PB - HAL
DO - 10.64898/2026.10.02.755967
UR - https://amu.hal.science/hal-05796678v1
AB - Bacteria employ molecular mimicry to hijack host cellular functions for their own benefit. Despite the wealth of data mapping human-bacteria interactions, a comprehensive view of how these networks are fine-tuned remains elusive. In particular, there have been no large-scale screenings measuring human-bacterial protein-protein binding affinities to explore their role in functional and pathological outcomes. Here, we report the largest quantitative interactome to date between the family of human PDZ domains and C-terminal PDZ-binding motifs (PBMs) in effectors from pathogenic and resident gut bacteria. We show that bacteria tailor effector sequences to bind PDZ domains with similar or higher binding affinities than human PBMs to hijack their associated cellular functions. For a subset of the dataset, we validate PDZ-PBM interactions with the corresponding full-length proteins and show that for pathogenic E. coli effector NleA, its C-terminal PBM is necessary for interactions with proteins involved in intracellular transport and membrane organization, probably impacting the host glycocalyx to favor infection. Finally, we show that motifs overlapping with effector PBMs target interaction modules other than PDZ domains, adding an additional layer of complexity to the host-microbe molecular dialogue.
ER -