Phosphorylation of the Autophagy Receptor Optineurin Restricts Salmonella Growth

By P. Wild, H. Farhan, David G. McEwan, Sebastian A. Wagner, V. Rogov, N. Brady, Benjamin Richter, Jelena Korać, O. Waidmann, Chunaram Choudhary and 3 more. Science, 2011

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Phosphorylation of an autophagy receptor restricts pathogenic cytosolic bacterial growth. Selective autophagy can be mediated via receptor molecules that link specific cargoes to the autophagosomal membranes decorated by ubiquitin-like microtubule-associated protein light chain 3 (LC3) modifiers. Although several autophagy receptors have been identified, little is known about mechanisms controlling their functions in vivo. In this work, we found that phosphorylation of an autophagy receptor, optineurin, promoted selective autophagy of ubiquitin-coated cytosolic Salmonella enterica. The protein kinase TANK binding kinase 1 (TBK1) phosphorylated optineurin on serine-177, enhancing LC3 binding affinity and autophagic clearance of cytosolic Salmonella. Conversely, ubiquitin- or LC3-binding optineurin mutants and silencing of optineurin or TBK1 impaired Salmonella autophagy, resulting in increased intracellular bacterial proliferation. We propose that phosphorylation of autophagy receptors might be a general mechanism for regulation of cargo-selective autophagy.

Subfields: Endocrinology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1060d7488ea387a7f7fd357f69ac86325f6323f3

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Citations in the corpus

An Overview of Autophagy: Morphology, Mechanism, and Regulation (2014, background): “NBR1 and OPTN are other receptors that function in targeting ubiquitinated proteins or pathogens to autophagosomes (75, 147).”
Autophagy in inflammation, infection, and immunometabolism (2021, background): “, 2016), including those that recognize LC3 on autophagosomal membranes (Wild et al., 2011) and ubiquitin on the cargo (Pilli et al.”
Autophagy: Renovation of Cells and Tissues (2011, background): “, 2009) and optineurin (Wild et al., 2011), mediate the degradation of invading microbes via their interaction with ubiquitination (Figure 3).”
Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria (2016, methodology): “TBK1 has been reported to regulate the autophagy receptors OPTN and p62 during bacterial infection (15, 17) and, more recently, during mitophagy (13, 23).”
TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation (2012, positive): “A recent study implicating TBK-1 via optineurin-sponsored events in the autophagic control of Salmonella upon escape into the cytosol (Wild et al., 2011) and our present work are in keeping with the report (Radtke et al., 2007) uncovering the role of TBK-1 in control of intracellular bacteria, in…”
Ubiquitination and selective autophagy (2012, background): “TBK1 is a serine/threonine kinase from the IKK family that has an antibacterial activity.91 Moreover, it was shown that TBK1 enhances LC3 binding to OPTN by phosphorylation of a conserved serine residue adjacent to the LIR motif of OPTN.92 Similar to NDP52 and TBK1 signalling, p62 interacts with aty”
The LIR motif – crucial for selective autophagy (2013, background): “Optineurin also recruits TBK1 to ubiquitylated Salmonella, resulting in the subsequent phosphorylation of optineurin at S177 located at the ‘any amino acid residue’ at position –1, which strongly enhances the binding to LC3B (Wild et al., 2011).”
Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia (2015, methodology): “In two subsequent PCRs with oligonucleotides FW and RV(2) or RV(3), respectively, bp 2139–2190 of wild-type TBK1 as well as a SalI restriction site were added to the 3′ end of the first PCR product.”
Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation (2014, background): “Optineurin regulates autophagosome maturation (16) and autophagic degradation of Salmonella and protein aggregates (15, 17).”
Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. (2016, background): “TBK1 and Optineurin also play important roles in xenophagy [49,58] and have been shown to contribute to inflammatory pathways [59,60], highlighting the complexity of neurodegeneration in ALS and glaucoma.”
Autophagy during viral infection — a double-edged sword (2018, background): “Here, pathogen specificity is mediated by xenophagy signalling receptors, such as p62 (sequestosome 1), next to of BRCA1 gene 1 protein (NBR1), calcium-binding and coiled-coil domain-containing protein 2 (NDP52; also known as CAlCoCo2) and optineurin, which are a subset of PRRs called p62/SQSTm1-lik”
Guidelines for the use and interpretation of assays for monitoring autophagy (2012, background): “In contrast, macroautophagy of these bacteria requires ubiquitination of target proteins (not yet identified) and recruitment of three ubiquitin-binding adaptor proteins, p62/SQSTM1,(572) NDP52(573) and OPTN.(574) Therefore, the currently available criteria to differentiate LAP from macroautophagy i”