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 non-toxigenic 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.

Abbreviations: ATG5: autophagy related 5; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; GST: glutathione S-transferase; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha; OMV: outer membrane vesicles; SQSTM1/p62: sequestosome 1; SCV: Salmonella containing vesicle; TECPR1: tectonin beta-propeller repeat containing 1; YhjJ: hypothetical zinc-protease.

KEYWORDS:

• Autophagy
• bacterial regulation of host
• MAP1LC3/LC3
• MAP1LC3/LC3-interacting region motif
• microbiota
• CALCOCO2/NDP52
• SQSTM1/p62
• pathogen recognition
• interplay

Acknowledgments

Authors are grateful for the discussions with the members of the Korcsmaros and Nezis groups. IN (Warwick, UK) was supported by BBSRC grants BB/L006324/1 and BB/P007856/1, TK by a fellowship tin computational biology at Earlham Institute (Norwich, UK) in partnership with the Quadram Institute (Norwich, UK), and strategically supported by Biotechnological and Biosciences Research Council, UK (BB/J004529/1 and BB/P016774/1). LG was supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership (grant BB/M011216/1).

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplemental data

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) [BB/P007856/1]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/P016774/1]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J004529/1]; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/L006324/1].