The multifunctional adaptor optineurin has been implicated in an increasing number of protein-protein interactions and cellular functions ever since its first identification as a binding partner for an adenoviral protein (1). Most—if not all—optineurin functions require its ubiquitin-binding domain in its C-terminus, which binds to K63- and/or M1-polyubiquinated proteins, allowing it to act, for example, as an adaptor during inflammatory signaling, autophagy, and vesicle trafficking (2–4). The interest in optineurin intensified after the identification of various mutations and polymorphisms in several human diseases, including primary open-angle glaucoma, amyotrophic lateral sclerosis (ALS), Paget's disease of the bone, and Crohn's disease. With their distinct yet unresolved pathogenesis, and complex genetic and environmental risk factors, these diseases seem unrelated at first. ALS, glaucoma, or Paget's disease are not traditionally regarded as immune-mediated diseases; however, the emerging evidence pinpoints immune system disfunction as their common denominator (5, 6). The aim of this Research Topic was to explore the role(s) of optineurin on a host of diverse cellular pathways that are directly or indirectly linked to the immune response. The articles cover immune signaling, cell death, membrane trafficking, autophagy of intracellular bacteria (xenophagy), damaged mitochondria (mitophagy), and protein aggregates.AS thanks the Medical Research Council (MR/L000261/1) for financial support. FB thanks the Medical Research Council (MR/K000888/1 and MR/N000048/1) and the BBSRC (BB/R001316/1). IM thanks the Croatian Science Foundation (IP-2018-01-8563) and the support of the University of Rijeka (18-211-1369)

Buss, Folma

Munitic, Ivana

Smith, Andrew M

English

Smith, AM

Buss, F

Munitic, I

UCL Discovery

EDITORIALpublished: 11 December 2019doi: 10.3389/fimmu.2019.02803Frontiers in Immunology | www.frontiersin.org 1 December 2019 | Volume 10 | Article 2803Edited and reviewed by:Pietro Ghezzi,Brighton and Sussex Medical School,United Kingdom*Correspondence:Ivana Muniticivana.munitic@biotech.uniri.hrSpecialty section:This article was submitted toInflammation,a section of the journalFrontiers in ImmunologyReceived: 25 October 2019Accepted: 14 November 2019Published: 11 December 2019Citation:Smith AM, Buss F and Munitic I (2019)Editorial: The Role of Optineurin inImmunity and Immune-MediatedDiseases. Front. Immunol. 10:2803.doi: 10.3389/fimmu.2019.02803Editorial: The Role of Optineurin inImmunity and Immune-MediatedDiseasesAndrew M. Smith 1, Folma Buss 2 and Ivana Munitic 3*1Microbial Diseases, Eastman Dental Institute, UCL, London, United Kingdom, 2Cambridge Institute for Medical Research,University of Cambridge, Cambridge, United Kingdom, 3 Laboratory for Molecular Immunology, Department of Biotechnology,University of Rijeka, Rijeka, CroatiaKeywords: optineurin, innate immunity, inflammation, autophagy, vesicle traffickingEditorial on the Research TopicThe Role of Optineurin in Immunity and Immune-Mediated DiseasesThe multifunctional adaptor optineurin has been implicated in an increasing number of protein-protein interactions and cellular functions ever since its first identification as a binding partnerfor an adenoviral protein (1). Most—if not all—optineurin functions require its ubiquitin-bindingdomain in its C-terminus, which binds to K63- and/or M1-polyubiquinated proteins, allowing it toact, for example, as an adaptor during inflammatory signaling, autophagy, and vesicle trafficking(2–4). The interest in optineurin intensified after the identification of various mutations andpolymorphisms in several human diseases, including primary open-angle glaucoma, amyotrophiclateral sclerosis (ALS), Paget’s disease of the bone, and Crohn’s disease. With their distinct yetunresolved pathogenesis, and complex genetic and environmental risk factors, these diseases seemunrelated at first. ALS, glaucoma, or Paget’s disease are not traditionally regarded as immune-mediated diseases; however, the emerging evidence pinpoints immune system disfunction as theircommon denominator (5, 6). The aim of this Research Topic was to explore the role(s) of optineurinon a host of diverse cellular pathways that are directly or indirectly linked to the immune response.The articles cover immune signaling, cell death, membrane trafficking, autophagy of intracellularbacteria (xenophagy), damaged mitochondria (mitophagy), and protein aggregates.In their mini review, Slowicka and van Loo give an overview of the various lines of evidenceimplicating optineurin in the regulation of the immune response. Due to its high homology to theNF-κB essential modulator (NEMO), optineurin was initially considered to be a negative regulatorof NF-κB, a major proinflammatory transcription factor (7, 8). However, NF-κB hyperactivationwas not identified in a range of primary cells from loss-of-function optineurin mouse models(9–12). This unexpected finding is further analyzed by Liu et al. through an investigation of theoverexpression of the common optineurin ALS mutations in mouse embryonic fibroblasts; this isdemonstrated to lead to higher NF-κB activation and inflammatory cytokine secretion. They followthis up by delivering lentiviruses carrying patient ubiquitin-binding deficient E478G mutationor wild-type optineurin into the mouse motor cortex, showing that expression of the mutantoptineurin triggers immune cell infiltration, microgliosis, proinflammatory cytokine secretion, andimpaired motor functions. Outlioua et al. review the role of optineurin in regulating antiviraltype I interferon (IFN) production through activation of TANK-binding kinase 1 (TBK1) atthe Golgi apparatus. TBK1 is K63-polyubiquitinated upon pathogen or damage-sensing, whichallows TBK1 to be recognized and to dock onto optineurin by a bipartite interaction via itsubiquitin-binding site and coiled-coil regions. Optineurin thereby serves as an adaptor for TBK1trans-autophosphorylation and activation. The authors also emphasize that the interaction betweenSmith et al. Editorial: Optineurin in Immunityoptineurin and TBK1 is multifaceted as optineurin itselfbecomes phosphorylated by TBK1, which is crucial for itsrole as an autophagy receptor and to its interaction with themicrotubule-associated protein 1A/1B light chain 3B (LC3) inautophagosomal membranes.Several publications elaborate on the role of optineurin inautophagy, which extends beyond its function as an autophagyreceptor for the recruitment of LC3-positive membranes toubiquitinated cargo. The central role of optineurin in diversemembrane trafficking pathways (autophagosome-lysosomefusion, vesicle secretion, etc.) and the importance of differentbinding partners is comprehensively summarized by Ryan andTumbarello. This review specifically highlights the central roleof optineurin in selective autophagy and how its disfunction islinked to neuronal cell death and neurodegeneration. Weil et al.have compiled an extensive review on mitophagy and the roleof optineurin in mitochondrial regulation and its implicationsin neurodegeneration and cancer. Abnormalities in mitophagyare associated with a number of diseases, including Parkinson’sdisease, ALS, primary open angle glaucoma, and cancer. Thecurrent understanding on how optineurin mutations found inALS and glaucoma impact on mitophagy are covered in themanuscript. Finally, the authors discuss whether the potentialrole of optineurin in mitophagy is also linked to other diseases,such as cancer and inflammatory bowel disease.Toth and Atkin focus their review initially on the multiplecellular mechanisms of optineurin, and they then proceed toput these processes in context with ALS and glaucoma. Disease-associated optineurinmutations and the impact these have on thephysiological processes of inflammatory signaling, endoplasmicreticulum stress, secretion, autophagy, and cell viability arediscussed in detail. The review highlights the complexity ofneurodegeneration and how optineurin in combination withother key disease-associated molecules, such as SOD1 and TBK1,is thought to contribute to disease progression. The reviewby Swarup and Sayyad specifically highlights the link betweenoptineurin and glaucoma. The authors discuss the impact ofthe glaucoma-associated mutants, the E50K and M98K, on thecellular functions of optineurin. Interestingly, these glaucoma-specific mutations induce pathologies only in retinal cellsdespite optineurin being widely expressed in different cell typesand tissues.Tschurtschenthaler and Adolph’s mini review brings togetherthe current literature dealing with optineurin and intestinalinflammation and places them in the context of Crohn’s diseaseetiology. Optineurin has been reported to play a major role inxenophagy, the regulation of endoplasmic reticulum stress, andthe facilitation of pro-inflammatory cytokine secretion, all ofwhich have a major impact on the intestine and have previouslybeen associated with the development of Crohn’s disease (13).The review covers findings from a number of studies that supportan active role for optineurin in intestinal immunity and describethe chronic bowel inflammation that develops in its absence.Finally, they describe how optineurin limits the accumulation ofan endoplasmic reticulum-anchored inflammatory signaling hubwithin the intestinal epithelium, which prevents the developmentof spontaneous enteritis. The precise role of optineurin inCrohn’s disease is still unclear, and the authors thus highlight theneed for further investigation.This collection highlights the wide range of functionsassociated with optineurin, many of which are crucial formaintaining tissue homeostasis by use of the innate immunesystem. This may explain why optineurin mutations arefound in a wide array of chronic disorders. Many openquestions remain, especially whether optineurin mutationsand/or polymorphisms found in patients act as primary orcontributing factors in disease pathogenesis. We hope thatfurther insight into how the mechanisms by which optineurinloss- and/or gain-of-function causes different disorders will incitenew immunomodulatory therapies.AUTHOR CONTRIBUTIONSAll authors designed, drafted, and approved the final version ofthe manuscript.ACKNOWLEDGMENTSAS thanks the Medical Research Council (MR/L000261/1)for financial support. FB thanks the Medical ResearchCouncil (MR/K000888/1 and MR/N000048/1) and the BBSRC(BB/R001316/1). IM thanks the Croatian Science Foundation(IP-2018-01-8563) and the support of the University ofRijeka (18-211-1369).REFERENCES1. Li Y, Kang J, Horwitz MS. Interaction of an adenovirus E3 14.7-kilodaltonprotein with a novel tumor necrosis factor alpha-inducible cellular proteincontaining leucine zipper domains. Mol Cell Biol. (1998) 18:1601–10.doi: 10.1128/MCB.18.3.16012. Tumbarello DA, Waxse BJ, Arden SD, Bright NA, Kendrick-Jones J, Buss F.Autophagy receptors link myosin VI to autophagosomes to mediate Tom1-dependent autophagosomematuration and fusion with the lysosome.Nat CellBiol. (2012) 14:1024–35. doi: 10.1038/ncb25893. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR,et al. Phosphorylation of the autophagy receptor optineurin restrictsSalmonella growth. Science. (2011) 333:228–33. doi: 10.1126/science.12054054. Markovinovic A, Cimbro R, Ljutic T, Kriz J, Rogelj B, Munitic I. Optineurinin amyotrophic lateral sclerosis: multifunctional adaptor protein at thecrossroads of different neuroprotective mechanisms. Prog Neurobiol. (2017)154:1–20. doi: 10.1016/j.pneurobio.2017.04.0055. Smith AM, Sewell GW, Levine AP, Chew TS, Dunne J, O’Shea NR, et al.Disruption of macrophage pro-inflammatory cytokine release in Crohn’sdisease is associated with reduced optineurin expression in a subset ofpatients. Immunology. (2015) 144:45–55. doi: 10.1111/imm.123386. Albagha OM, Visconti MR, Alonso N, Langston AL, Cundy T, Dargie R,et al. Genome-wide association study identifies variants at CSF1, OPTN andTNFRSF11A as genetic risk factors for Paget’s disease of bone. Nat Genet.(2010) 42:520–4. doi: 10.1038/ng.5627. Schwamborn K, Weil R, Courtois G, Whiteside ST, Israel A. Phorbol estersand cytokines regulate the expression of the NEMO-related protein, aFrontiers in Immunology | www.frontiersin.org 2 December 2019 | Volume 10 | Article 2803Smith et al. Editorial: Optineurin in Immunitymolecule involved in a NF-kappa B-independent pathway. J Biol Chem. (2000)275:22780–9. doi: 10.1074/jbc.M0015002008. Zhu G, Wu CJ, Zhao Y, Ashwell JD. Optineurin negativelyregulates TNFalpha- induced NF-kappaB activation by competingwith NEMO for ubiquitinated RIP. Curr Biol. (2007) 17:1438–43.doi: 10.1016/j.cub.2007.07.0419. Gleason CE, Ordureau A, Gourlay R, Arthur JS, Cohen P. Polyubiquitinbinding to optineurin is required for optimal activation of TANK-bindingkinase 1 and production of interferon β. J Biol Chem. (2011) 286:35663–74.doi: 10.1074/jbc.M111.26756710. Munitic I, Giardino Torchia ML, Meena NP, Zhu G, Li CC, Ashwell JD.Optineurin insufficiency impairs IRF3 but not NF-κB activation in immunecells. J Immunol. (2013) 191:6231–40. doi: 10.4049/jimmunol.130169611. Slowicka K, Vereecke L, Mc Guire C, Sze M, Maelfait J, Kolpe A, et al.Optineurin deficiency in mice is associated with increased sensitivity toSalmonella but does not affect proinflammatory NF-kappaB signaling. Eur JImmunol. (2016) 46:971–80. doi: 10.1002/eji.20154586312. Markovinovic A, Ljutic T, Beland LC, Munitic I. Optineurin insufficiencydisbalances proinflammatory and anti-inflammatory factors by reducingmicroglial IFN-beta responses. Neuroscience. (2018) 388:139–51.doi: 10.1016/j.neuroscience.2018.07.00713. Segal AW.Making sense of the cause of Crohn’s – a new look at an old disease.F1000Research. (2016) 5:2510. doi: 10.12688/f1000research.9699.1Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2019 Smith, Buss andMunitic. This is an open-access article distributedunder the terms of the Creative Commons Attribution License (CC BY). The use,distribution or reproduction in other forums is permitted, provided the originalauthor(s) and the copyright owner(s) are credited and that the original publicationin this journal is cited, in accordance with accepted academic practice. No use,distribution or reproduction is permitted which does not comply with these terms.Frontiers in Immunology | www.frontiersin.org 3 December 2019 | Volume 10 | Article 2803

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