Targeted interplay between bacterial pathogens and host autophagy

Abstract

Due to the critical role played by autophagy in pathogen clearance, pathogens have developed diverse strategies to subvert it. Despite previous key findings of bacteria-autophagy interplay, asystems-level insight into selective targeting by the host and autophagy modulation by the pathogens is lacking. We predicted potential interactions between human autophagy proteins and effector proteins from 56 pathogenic bacterial species by identifying bacterial proteins predicted to have recognition motifs for selective autophagy receptors SQSTM1/p62, CALCOCO2/ NDP52 and MAP1LC3/LC3. Using structure-based interaction prediction, we identified bacterial proteins capable to modify core autophagy components. Our analysis revealed that autophagy receptors in general potentially target mostly genus-specific proteins, and not those present in multiple genera. The complementarity between the predicted SQSTM1/p62 and CALCOCO2/NDP52 targets, which has been shown for Salmonella, Listeria and Shigella, could be observed across other pathogens. This complementarity potentially leaves the host more susceptible to chronic infections upon the mutation of autophagy receptors. Proteins derived from enterotoxigenic and nontoxigenic Bacillus outer membrane vesicles indicated that autophagy targets pathogenic proteins rather than non-pathogenic ones. We also observed apathogen-specific pattern as to which autophagy phase could be modulated by specific genera. We found intriguing examples of bacterial proteins that could modulate autophagy, and in turn being targeted by autophagy as ahost defense mechanism. We confirmed experimentally an interplay between a Salmonella protease, YhjJ and autophagy. Our comparative meta-analysis points out key commonalities and differences in how pathogens could affect autophagy and how autophagy potentially recognizes these pathogenic effectors.

MicrobioLink: An integrated computational pipeline to infer functional effects of microbiome-host interactions

“…The next step is the interaction prediction. In this step, we compare the annotated domains and motifs from the compiled bacterial and host proteins with the databases DOMINE [38] and ELM [39], which respectively contain high-confidence lists of domain-domain and domain-motif pairs already known to interact [18,40,41]. This procedure helps determine which bacterial proteins via their respective domains interact with host receptor proteins.…”

“…This is performed by excluding interactions involving motifs outside disordered interactions (using IUPRED [44]) and/or within globular domains (from PFAM [45], InterPro [46]). Some studies such as [18][19][20] have already successfully used this structure-based approach to predict PPIs between microbial and host proteins, and validated the PPIs experimentally.…”

“…Such crosstalks are mediated by molecular interactions between various molecular components expressed by the host and the microbiome. Bacterial molecules, such as metabolites [15], proteins [16,17,[17][18][19][20] and small RNAs [21], can interact with host molecules, and launch an intracellular cascade able to modulate biological processes by affecting key host genes and proteins. Next to metabolite mediated interactions, protein-protein interactions (PPIs) are one of the most relevant and reported types of molecular interactions between the host and microbes [17][18][19][20].…”

“…Bacterial molecules, such as metabolites [15], proteins [16,17,[17][18][19][20] and small RNAs [21], can interact with host molecules, and launch an intracellular cascade able to modulate biological processes by affecting key host genes and proteins. Next to metabolite mediated interactions, protein-protein interactions (PPIs) are one of the most relevant and reported types of molecular interactions between the host and microbes [17][18][19][20]. However, experimental techniques to probe inter-species PPIs are time consuming and have limitations imposed by cost [2,14,16,[22][23][24].…”

H. pyloriinfection inhibits autophagy to aggravate DNA damage by p62-mediated Rad51 ubiquitination

“…In response to various cellular stress, activation of autophagy is crucial for maintaining cellular energy levels through synthesis, degradation and recycle of constituents. Induction of autophagy serves as a cell defence mechanism against intracellular pathogenic microorganisms (Sudhakar, Jacomin et al, 2019). Several microbes such as Listeria monocytogenes have been shown to stimulate formation of autophagosomes, which in turn initiates bacterial degradation (Huang & Brumell, 2014).…”