Abstract
Macrophages are highly plastic cells with critical roles in immunity, cancer, and tissue homeostasis, but how these distinct cellular fates are triggered by environmental cues is poorly understood. To uncover how primary murine macrophages respond to bacterial pathogens, we globally assessed changes in post-translational modifications of proteins during infection with Mycobacterium tuberculosis, a notorious intracellular pathogen. We identified hundreds of dynamically regulated phosphorylation and ubiquitylation sites, indicating that dramatic remodeling of multiple host pathways, both expected and unexpected, occurred during infection. Most of these cellular changes were not captured by mRNA profiling, and included activation of ubiquitin-mediated autophagy, an evolutionarily ancient cellular antimicrobial system. This analysis also revealed that a particular autophagy receptor, TAX1BP1, mediates clearance of ubiquitylated Mtb and targets bacteria to LC3-positive phagophores. These studies provide a new resource for understanding how macrophages shape their proteome to meet the challenge of infection.
Highlights
Mycobacterium tuberculosis (Mtb) is among the most successful human pathogens and forms longterm, chronic infections that can span decades
To identify new innate immune pathways modulated during Mtb infection, we sought to obtain a deep data set of changes in host protein abundance and post-translational modifications during a time course of macrophage infection
Similar to prior results showing that p62-deficient macrophages are impaired in the targeting of Shigella vacuolar remnants to ubiquitin (Dupont et al, 2009), we found decreased targeting of Mtb to ubiquitin (FK2) in p62-/- macrophages compared to wild-type cells, consistent with an early role for p62 in signal amplification required for full cargo ubiquitylation (Figure 5B; Peng et al, 2017)
Summary
Mycobacterium tuberculosis (Mtb) is among the most successful human pathogens and forms longterm, chronic infections that can span decades. The mechanisms by which Mtb exploits macrophages and the cell-intrinsic immune effectors that limit Mtb replication, as well as how these two properties are balanced during chronic infection, is only partially understood. Uncovering these intimate interactions, which have coevolved over nearly 70,000 years (Comas et al, 2013), may reveal novel therapeutic intervention strategies to treat the nearly ten million people who fall ill to tuberculosis infection each year (World Health Organization, 2018). Mtb infection of macrophages engages several pattern recognition receptors including toll-like receptor 2 (TLR2) leading to expression of inflammatory mediators
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