Ubiquilins and Mtb Xenophagy
Macrophages are able to partially control Mtb through a degradative process called autophagy. Understanding how bacteria are cleared by autophagy is a focus of intense research effort. Autophagy is activated by the cytokine interferon-gamma, which promotes control of Mtb infection (1). How the tubercle bacilli are targeted to the autophagy pathway remains unclear. We found that 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 (2). We found that UBQLN1 can interact with Mtb surface proteins and associates with the bacilli in vitro (3). In IFN-gamma activated macrophages, UBQLN1 co-localizes with Mtb and promotes the anti-mycobacterial activity of IFN-gamma. Our data suggest a model in which activating autophagy with IFN-gamma promotes UBQLN1 recruitment to Mtb, which in turn leads to recruitment of the autophagy machinery, autophagy-mediated degradation of the bacteria, and antigen presentation. Since IFN-gamma is critical in human control of Mtb, our study suggests that polymorphisms in ubiquilins, known to influence susceptibility to neurodegenerative illnesses, might also play a role in host defense against Mtb. Ongoing work involves elucidating the molecular mechanism behind Ubqln1 function and its role in host susceptibility to Mtb.
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2. Takalo M, Haapasalo A, Natunen T, Viswanathan J, Kurkinen KM, Tanzi RE, et al. Targeting ubiquilin-1 in Alzheimer's disease. Expert Opin Ther Targets. 2013;17(7):795-810. doi: 10.1517/14728222.2013.791284. PubMed PMID: 23600477.
3. Sakowski E, Koster S, Portal Celhay C, Park H, Shrestha E, Hetzenecker SE, Maurer K, Cadwell K, Philips JA. Ubiquilin 1 Promotes Cytokine-induced Xenophagy of Mycobacterium tuberculosis, PLoS Pathogens, 2015. Jul 30;11(7):e1005076. doi: 10.1371/journal.ppat.1005076.