Dr. Yaown Wu
Phone: +49 (231) 133-2943
Yang A, Pantoom S, Wu YW (2017). Elucidation of the anti-autophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins.
Researchers from the Chemical Genomics Centre (CGC) of the Max Planck Society, Germany, have unraveled how the Legionella bacteria outsmart the human body’s defence termed autophagy.
April 25, 2017
Infection is a general problem in our everyday life. Our cells are able to fight infections by “eating” bacteria via an evolutionary conserved cellular self-eating process called autophagy. However, some virulent bacteria evolved mechanisms to avoid this process in order to survive and proliferate in the host cell. One of them is Legionella pneumophila. “Infection with Legionella is a common cause of community and hospital-acquired pneumonia with a death rate up to 30%", says senior author Dr. Yaowen Wu, group leader at CGC.
Legionella tricks the cells to avoid being eaten by producing a molecule called RavZ. But until now it was not known exactly how RavZ achieves this effect. "We set out to understand the molecular mechanism by which Legionella evades host autophagy, specifically by establishing how RavZ breaks apart a key molecule in the autophagy process called LC3-PE", Dr. Yaowen Wu explains. LC3-PE is crucial for one of the main events during autophagy, the creation of a membrane-bound bag that engulfs the pathogen. Analyzing interactions between LC3-PE and RavZ is extremely challenging because it is hard to isolate and modify LC3-PE.
‘Tweezers’ and ‘Scissors’
Wu’s team tackled this problem by preparing a series of semisynthetic LC3 ‘versions’ by chemical approaches and could thereby study the structure-function relationship of the host-pathogen interaction, published in the journal “eLife”. Using a combination of cell biological, biophysical and structural biological approaches, the research team has revealed an intriguing mechanism. “In order to avoid being eaten by our cells Legionella bacteria have evolved a very smart mechanism” Dr. Wu explains. “The effector RavZ functions as both ‘tweezers’ and ‘scissors’. It recognizes LC3 via its LC3-interacting region called LIR and then takes the lipidated LC3 protein out of the membrane before it cleaves the lipid from the protein. This unique mechanism ensures specificity of the action.”
“We hope that understanding this mechanism will be beneficial for the development of new drugs against infection by Legionella”, says Dr. Wu.