Listeriolysin O Regulates the Expression of Optineurin, an Autophagy Adaptor That Inhibits the Growth of Listeria monocytogenes

Puri, Madhu; Pietra, Luigi La; Mraheil, Mobarak Abu; Lucas, Rudolf; Chakraborty, Trinad; Pillich, Helena

doi:10.3390/toxins9090273

Cited by 16 publications

(10 citation statements)

References 36 publications

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“…In the case of Listeria monocytogenes , upregulation of optineurin occurs in response to the bacterial expression of listeriolysin O (LLO) ( 107 ), a pore-forming cytolysin that allows the bacteria to escape from a vacuolar compartment into the cytosol following host entry ( 108 ). Here, TBK1 activity enhances optineurin-mediated clearance of the pathogen, whilst a reduction in optineurin expression results in less autophagosomal clearance of L. monocytogenes ( 107 ). These data together are indicative of the importance of the TBK1–optineurin axis in the clearance of several pathogenic bacteria.…”

Section: Optineurin Regulation Of Autophagymentioning

confidence: 99%

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Ryan

Tumbarello

2018

Front. Immunol.

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Optineurin is a multifunctional adaptor protein intimately involved in various vesicular trafficking pathways. Through interactions with an array of proteins, such as myosin VI, huntingtin, Rab8, and Tank-binding kinase 1, as well as via its oligomerisation, optineurin has the ability to act as an adaptor, scaffold, or signal regulator to coordinate many cellular processes associated with the trafficking of membrane-delivered cargo. Due to its diverse interactions and its distinct functions, optineurin is an essential component in a number of homeostatic pathways, such as protein trafficking and organelle maintenance. Through the binding of polyubiquitinated cargoes via its ubiquitin-binding domain, optineurin also serves as a selective autophagic receptor for the removal of a wide range of substrates. Alternatively, it can act in an ubiquitin-independent manner to mediate the clearance of protein aggregates. Regarding its disease associations, mutations in the optineurin gene are associated with glaucoma and have more recently been found to correlate with Paget’s disease of bone and amyotrophic lateral sclerosis (ALS). Indeed, ALS-associated mutations in optineurin result in defects in neuronal vesicular localisation, autophagosome–lysosome fusion, and secretory pathway function. More recent molecular and functional analysis has shown that it also plays a role in mitophagy, thus linking it to a number of other neurodegenerative conditions, such as Parkinson’s. Here, we review the role of optineurin in intracellular membrane trafficking, with a focus on autophagy, and describe how upstream signalling cascades are critical to its regulation. Current data and contradicting reports would suggest that optineurin is an important and selective autophagy receptor under specific conditions, whereby interplay, synergy, and functional redundancy with other receptors occurs. We will also discuss how dysfunction in optineurin-mediated pathways may lead to perturbation of critical cellular processes, which can drive the pathologies of number of diseases. Therefore, further understanding of optineurin function, its target specificity, and its mechanism of action will be critical in fully delineating its role in human disease.

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Section: Optineurin Regulation Of Autophagymentioning

confidence: 99%

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Ryan

Tumbarello

2018

Front. Immunol.

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“…Also, C57BL/6 irf8 −/− mice displayed increased L. monocytogenes burden due to lower levels of autophagy, and it was proposed that the transcription factor IRF8 downstream from IFNγ controls the expression of seven of the autophagy genes during Listeria infection [64]. The autophagy adaptor optineurin is phosphorylated by the TANK binding kinase 1, which enhances its affinity for LC3 and L. monocytogenes degradation by autophagy in HeLa cells in an LLO-dependent fashion [65]. Macro-phage infection models suggested that autophagy can capture L. monocytogenes located in the phagosome, but after bacteria had started to replicate in the cytosol [62].…”

Section: Pathogens Differentially Interfere With the Inflammasomes Anmentioning

confidence: 99%

Checks and Balances between Autophagy and Inflammasomes during Infection

Seveau

Turner

Gavrilin

et al. 2018

Journal of Molecular Biology

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Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the serine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.

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“…The concordance of miRNA/mRNA regulation might indicates a role of this circuit in the activation of signaling pathways, synthesis of AMPs and the defense response of larvae against listerial infection. Optineurin is a receptor for autophagy and plays a major role in removal of intracellular bacteria (Wild et al, 2011 ; Puri et al, 2017 ). In agreement with previously described roles, we observed strong induction of optineurin, which is correlated with decreased expression of two regulatory miRNAs (miR-133 and miR-998).…”

Section: Discussionmentioning

confidence: 99%

Listeria monocytogenes Induces a Virulence-Dependent microRNA Signature That Regulates the Immune Response in Galleria mellonella

et al. 2017

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microRNAs (miRNAs) coordinate several physiological and pathological processes by regulating the fate of mRNAs. Studies conducted in vitro indicate a role of microRNAs in the control of host-microbe interactions. However, there is limited understanding of miRNA functions in in vivo models of bacterial infections. In this study, we systematically explored changes in miRNA expression levels of Galleria mellonella larvae (greater-wax moth), a model system that recapitulates the vertebrate innate immunity, following infection with L. monocytogenes. Using an insect-specific miRNA microarray with more than 2000 probes, we found differential expression of 90 miRNAs (39 upregulated and 51 downregulated) in response to infection with L. monocytogenes. We validated the expression of a subset of miRNAs which have mammalian homologs of known or predicted function. In contrast, non-pathogenic L. innocua failed to induce these miRNAs, indicating a virulence-dependent miRNA deregulation. To predict miRNA targets using established algorithms, we generated a publically available G. mellonella transcriptome database. We identified miRNA targets involved in innate immunity, signal transduction and autophagy, including spätzle, MAP kinase, and optineurin, respectively, which exhibited a virulence-specific differential expression. Finally, in silico estimation of minimum free energy of miRNA-mRNA duplexes of validated microRNAs and target transcripts revealed a regulatory network of the host immune response to L. monocytogenes. In conclusion, this study provides evidence for a role of miRNAs in the regulation of the innate immune response following bacterial infection in a simple, rapid and scalable in vivo model that may predict host-microbe interactions in higher vertebrates.

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Listeriolysin O Regulates the Expression of Optineurin, an Autophagy Adaptor That Inhibits the Growth of Listeria monocytogenes

Cited by 16 publications

References 36 publications

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Optineurin: A Coordinator of Membrane-Associated Cargo Trafficking and Autophagy

Checks and Balances between Autophagy and Inflammasomes during Infection

Listeria monocytogenes Induces a Virulence-Dependent microRNA Signature That Regulates the Immune Response in Galleria mellonella

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