TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation
By Manohar Pilli, J. Arko-Mensah, Marisa Ponpuak, Esteban A. Roberts, Sharon S. Master, M. Mandell, N. Dupont, Wojciech Ornatowski, Shanya Jiang, Steven B. Bradfute and 4 more. Immunity, 2012
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Summary Autophagy is a fundamental biological process of the eukaryotic cell contributing to diverse cellular and physiological functions including cell-autonomous defense against intracellular pathogens. Here we screened the Rab family of membrane trafficking regulators for effects on autophagic elimination of Mycobacterium tuberculosis var. bovis BCG and found that Rab8b and its downstream interacting partner, innate immunity regulator TBK-1, are required for autophagic elimination of mycobacteria in macrophages. TBK-1 was necessary for autophagic maturation. TBK-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on Ser-403, a residue essential for its role in autophagic clearance. A key pro-inflammatory cytokine, IL-1β, induced autophagy leading to autophagic killing of mycobacteria in macrophages and this IL-1β activity was dependent on TBK-1. Thus, TBK-1 is a key regulator of immunological autophagy and is responsible for the maturation of autophagosomes into lytic bactericidal organelles.
Subfields: Epidemiology, Immunology, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/31d92b1fafe7d1ae7902a519fe3e9a02dccbb446
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Citations in the corpus
- Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, neutral): “This complex acts as a GDP/GTP exchange factor (GEF) for the activation of Rab8 and Rab39, which are involved in the formation or maturation of autophagosomes (Pilli et al, 2012; Seto et al., 2013) and interacts with the autophagy receptors SQSTM1/p62 and OPTN (Sellier et al., 2016).”
- p62 links the autophagy pathway and the ubiqutin–proteasome system upon ubiquitinated protein degradation (2016, neutral): “K63 is a common marker in the autophagy process [40].”
- Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. (2014, background): “…(Weidberg et al., 2011); recruits additional components of the autophagic machinery to the phagophore (Alemu et al., 2012; Colecchia et al., 2012; Popovic et al., 2012); directly regulates closure of the phagophore via interaction with Cdc48/ p97/VCP (Krick et al., 2010); and, via interaction…”
- Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria (2016, background): “TBK1 has been reported to regulate the autophagy receptors OPTN and p62 during bacterial infection (15, 17) and, more recently, during mitophagy (13, 23).”
- Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy. (2013, background): “Coupling of the Keap1-Nrf2 System to Autophagy the ubiquitinated cargos (Matsumoto et al., 2011; Pilli et al., 2012).”
- Autophagy in inflammation, infection, and immunometabolism (2021, background): “, 2011) and ubiquitin on the cargo (Pilli et al., 2012) (Figure 2F).”
- The mitophagy pathway and its implications in human diseases (2023, background): “48,49 Through ubiquitination at K420 of P62, the recruited kelch-like ECH-associated protein 1 (Keap1)-Cullin-3 complex Fig.”
- Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways (2015, neutral): “Although we saw no enrichment of case variants in SQSTM1, variants in OPTN and TBK1were estimated to explain or contribute to 1.30% of cases in our data set when taken together (combined data set), suggesting an important subgroup of patients that may have a common biological etiology.”