title: Ubiquilin 1 Promotes IFN-γ-Induced Xenophagy of Mycobacterium tuberculosis.
abstract: The success of Mycobacterium tuberculosis (Mtb) as a pathogen rests upon its ability to grow intracellularly in macrophages. Interferon-gamma (IFN-γ) 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-γ-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-γ activated macrophages, UBQLN1 co-localizes with Mtb and promotes the anti-mycobacterial activity of IFN-γ. 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.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Erik T
authors.initials: ET
authors.lastname: Sakowski
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Stefan
authors.initials: S
authors.lastname: Koster
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Portal Celhay
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Elina
authors.initials: E
authors.lastname: Shrestha
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Stefanie E
authors.initials: SE
authors.lastname: Hetzenecker
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Katie
authors.initials: K
authors.lastname: Maurer
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America; Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Ken
authors.initials: K
authors.lastname: Cadwell
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, New York University School of Medicine, New York, New York, United States of America; Department of Microbiology, New York University School of Medicine, New York, New York, United States of America; Department of Pathology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Philips
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071183:Autophagy-Related Proteins; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; C538987:UBQLN1 protein, mouse; D007371:Interferon-gamma