Ubiquilin 1 Promotes IFN-[gamma]-Induced Xenophagy of Mycobacterium tuberculosis: e1005076

The success of Mycobacterium tuberculosis (Mtb) as a pathogen rests upon its ability to grow intracellularly in macrophages. Interferon-gamma (IFN-[gamma]) is critical in host defense against Mtb and stimulates macrophage clearance of Mtb through an autophagy pathway. Here we show that the host prot...

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Bibliographic Details
Published in:PLoS pathogens 2015-07, Vol.11 (7)
Main Authors: Sakowski, Erik T, Koster, Stefan, Celhay, Cynthia Portal, Park, Heidi S, Shrestha, Elina, Hetzenecker, Stefanie E, Maurer, Katie, Cadwell, Ken, Philips, Jennifer A
Format: Article
Language:English
Subjects:
Autophagy
Bacteria
Charitable foundations
Colleges & universities
Experiments
Funding
Infections
Proteins
Tuberculosis
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Summary:The success of Mycobacterium tuberculosis (Mtb) as a pathogen rests upon its ability to grow intracellularly in macrophages. Interferon-gamma (IFN-[gamma]) is critical in host defense against Mtb and stimulates macrophage clearance of Mtb through an autophagy pathway. Here we show that the host protein ubiquilin 1 (UBQLN1) promotes IFN-[gamma]-mediated autophagic clearance of Mtb. Ubiquilin family members have previously been shown to recognize proteins that aggregate in neurodegenerative disorders. We find that UBQLN1 can interact with Mtb surface proteins and associates with the bacilli in vitro. In IFN-[gamma] activated macrophages, UBQLN1 co-localizes with Mtb and promotes the anti-mycobacterial activity of IFN-[gamma]. The association of UBQLN1 with Mtb depends upon the secreted bacterial protein, EsxA, which is involved in permeabilizing host phagosomes. In autophagy-deficient macrophages, UBQLN1 accumulates around Mtb, consistent with the idea that it marks bacilli that traffic through the autophagy pathway. Moreover, UBQLN1 promotes ubiquitin, p62, and LC3 accumulation around Mtb, acting independently of the E3 ligase parkin. In summary, we propose a model in which UBQLN1 recognizes Mtb and in turn recruits the autophagy machinery thereby promoting intracellular control of Mtb. Thus, polymorphisms in ubiquilins, which are known to influence susceptibility to neurodegenerative illnesses, might also play a role in host defense against Mtb.
ISSN:1553-7366
1553-7374
DOI:10.1371/journal.ppat.1005076