Regulation of autophagy-related mechanisms during bacterial infection

Xie, J. (2023)

Doctoral Thesis

Autophagy is a fundamental degradative process, maintaining cellular homeostasis and functions in host defense against intracellular pathogens, including mycobacteria and Salmonella. The thesis investigated the function of an regulator of antibacterial autophagy, Damage Regulated Autophagy Modulator 1 (DRAM1) against infection and shows that DRAM1 restricts bacterial growth not only through canonical antibacterial autophagy (xenophagy) but also promotes an autophagy-related pathway, named LC3-associated phagocytosis (LAP). The function of DRAM1 in restricting bacterial proliferation is independent from the recognition of bacteria by xenophagy receptors. Mechanistically, DRAM1 promotes the infection-induced activation of autophagy and LAP as well as the maturation of bacteria-containing vesicles in both pathways. This maturation process, stimulated by DRAM1, involves multiple vesicle fusion steps directing bacteria to lysosomes. Through this maturation process, DRAM1 delivers the cytosolic protein Fau to bacteria-containing vesicles, where it serves as a precursor for antimicrobial peptides. The underlying mechanism may be explained by the discovery of an interaction between DRAM1 and the SNARE protein VTI1B. Overall, the work in this thesis contributes to ongoing research into the potential application of autophagy modulation as a host-directed therapy against infectious diseases.

• Mycobacteria
• Tuberculosis
• Autophagy
• Xenophagy
• LC3- associated phagocytosis
• DRAM1
• p62
• OPTN
• Vesicle fusions
• Anti-microbial peptide

• All authors: Xie, J.
• Supervisor: Meijer, A.H.; Schaaf, M.J.M.
• Committee: Wezel, G.P. van; Spaink, H.P.; Ram, A.F.J.; Barisch, C.; Puri, D.
• Qualification: Doctor (dr.)
• Awarding Institution: Institute of Biology Leiden (IBL), Faculty of Science, Leiden University
• Date: 2023-12-05
• ISBN (print): 9789464696745