The <scp>TBK</scp>1‐binding domain of optineurin promotes type I interferon responses

Meena, Netra Pal; Zhu, Guozhi; Mittelstadt, Paul R.; Torchia, Maria Letizia Giardino; Pourcelot, Marie; Arnoult, Damien; Ashwell, Jonathan D.; Munitić, Ivana

doi:10.1002/1873-3468.12176

Cited by 33 publications

(20 citation statements)

References 39 publications

(83 reference statements)

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“…OPTN is associated to Golgi apparatus through an interaction with Rab8 and the interacting domain of OPTN is localized between amino acids 141–209, comprising therefore Ser177 [ 43 ]. After TBK1 activation, the phosphorylation of OPTN [ 40 , 44 ] may disrupt the association between OPTN and Rab8, therefore allowing TBK1-OPTN complexes [ 44 ] to leave the Golgi membranes to phosphorylate MAVS or TRIF at the mitochondria or endosomes, respectively, for IRF3 activation [ 34 ]. Our observation that p-TBK1 S172 accumulates at the centrosome at late time points after RLR activation strongly suggests that the active kinase is released from the Golgi membranes after its initial trans -autophosphorylation at this organelle.…”

Section: Discussionmentioning

confidence: 99%

The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing

et al. 2016

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BackgroundAfter viral infection and the stimulation of some pattern-recognition receptors, TANK-binding kinase I (TBK1) is activated by K63-linked polyubiquitination followed by trans-autophosphorylation. While the activated TBK1 induces type I interferon production by phosphorylating the transcription factor IRF3, the precise molecular mechanisms underlying TBK1 activation remain unclear.ResultsWe report here the localization of the ubiquitinated and phosphorylated active form of TBK1 to the Golgi apparatus after the stimulation of RIG-I-like receptors (RLRs) or Toll-like receptor-3 (TLR3), due to TBK1 K63-linked ubiquitination on lysine residues 30 and 401. The ubiquitin-binding protein optineurin (OPTN) recruits ubiquitinated TBK1 to the Golgi apparatus, leading to the formation of complexes in which TBK1 is activated by trans-autophosphorylation. Indeed, OPTN deficiency in various cell lines and primary cells impairs TBK1 targeting to the Golgi apparatus and its activation following RLR or TLR3 stimulation. Interestingly, the Bluetongue virus NS3 protein binds OPTN at the Golgi apparatus, neutralizing its activity and thereby decreasing TBK1 activation and downstream signaling.ConclusionsOur results highlight an unexpected role of the Golgi apparatus in innate immunity as a key subcellular gateway for TBK1 activation after RNA virus infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0292-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing

et al. 2016

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“…5 ) ( Markovinovic et al , 2018 ). Optineurin acts as an adaptor protein necessary for optimal TBK1 activation in various other innate immune cell subsets, suggesting that they likely act on the same axis in the pathogenesis of ALS ( Munitic et al , 2013 ; Meena et al , 2016 ; Pourcelot et al , 2016 ). Moreover, previous findings linked optineurin deficiency with diminished acute immune response and neutrophil recruitment to the site of infection in mice ( Chew et al , 2015 ; Smith et al , 2015 ), hence opening a possibility that inadequate first response to damage due to disruption in the optineurin-TBK1 axis could trigger neurodegeneration.…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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“…Furthermore, OPTN was shown to be regulated by and control type I IFN responses ( 7 , 29 , 35 ). Production of type I IFNs is the primary response to bacterial and viral infections ( 36 ).…”

Section: The Selective Autophagy Receptor Optn In Healthmentioning

confidence: 99%

“…Production of type I IFNs is the primary response to bacterial and viral infections ( 36 ). Specifically, upon recognition of pathogen-associated molecular patterns by toll-like receptors or RIG-I-like receptors, IFN regulatory factor 3 (IRF3) becomes phosphorylated by TANK-binding kinase 1 (TBK1) and translocates to the nucleus, which leads to the transcription of type I IFN response genes ( 7 ). OPTN binds to TBK1 to support IRF3 activation and production of type I IFNs ( 34 ).…”

Section: The Selective Autophagy Receptor Optn In Healthmentioning

confidence: 99%

The Selective Autophagy Receptor Optineurin in Crohn’s Disease

Tschurtschenthaler

Adolph

2018

Front. Immunol.

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Autophagy is a pathway that allows cells to target organelles, protein complexes, or invading microorganisms for lysosomal degradation. The specificity of autophagic processes is becoming increasingly recognized and is conferred by selective autophagy receptors such as Optineurin (OPTN). As an autophagy receptor, OPTN controls the clearance of Salmonella infection and mediates mitochondrial turnover. Recent studies demonstrated that OPTN is critically required for pathogen clearance and an appropriate cytokine response in macrophages. Moreover, OPTN emerges as a critical regulator of inflammation emanating from epithelial cells in the intestine. OPTN directly interacts with and promotes the removal of inositol-requiring enzyme 1α, a central inflammatory signaling hub of the stressed endoplasmic reticulum (ER). Perturbations of ER and autophagy functions have been linked to inflammatory bowel disease (IBD) and specifically Crohn’s disease. Collectively, these studies may explain how perturbations at the ER can be resolved by selective autophagy to restrain inflammatory processes in the intestine and turn the spotlight on OPTN as a key autophagy receptor. This review covers a timely perspective on the regulation and function of OPTN in health and IBD.

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The TBK1‐binding domain of optineurin promotes type I interferon responses

Cited by 33 publications

References 39 publications

The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing

The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

The Selective Autophagy Receptor Optineurin in Crohn’s Disease

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