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4
Significant divergence in mammalian host genes
requirements for A-B toxins traffic revealed by genomewide
RNAi screens
Frederic Bard 1
Institute of Molecular and Cell Biology 1
Abstract:
Retrograde traffic flows from the plasma membrane to the ER via the endosomes and the Golgi
apparatus. It is essential to maintain cellular homeostasis and is also subverted by various
pathogens and toxins, such as Ricin and Pseudomonas Exotoxin (PE). To molecularly
characterize the retrograde traffic, we screened human cells by RNAi at the genome-wide level
for factors required for Ricin and PE intoxication. The host genetic requirements appear
strikingly different between both toxins with only about 13% common factors out of the 2038
genes identified. Among known regulators of membrane traffic, the VPS35-Retromer complex is
specifically required for PE and the TRAPP complex for Ricin. Similarly, at the ER level, Ricin
and PE interact with largely different subsets of potential ERAD factors, including the Derlins
for Ricin and the Sec61 translocon for PE. Off-target effect was excluded for 178 of the most
potent regulators, which have for the most part no or little prior link with retrograde traffic,
such as several factors of the Cullin-Ring Ligases family. ERGIC2 is among the small set of
factors common for both toxins and is essential for toxin and general Golgi to ER traffic. In
addition to an increased understanding of the retrograde traffic pathways, our study provides a
unique resource for the future development of toxins antidotes.