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dc.contributor.authorFreihat, L A
dc.contributor.authorWheeler, J I
dc.contributor.authorWong, Aloysius Tze
dc.contributor.authorTurek, I
dc.contributor.authorManallack, D T
dc.contributor.authorIrving, H R
dc.date.accessioned2019-11-20T07:08:20Z
dc.date.available2019-11-20T07:08:20Z
dc.date.issued2019-10-31
dc.identifier.citationFreihat, L. A., Wheeler, J. I., Wong, A., Turek, I., Manallack, D. T., & Irving, H. R. (2019). IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity. Scientific Reports, 9(1). doi:10.1038/s41598-019-51913-3
dc.identifier.doi10.1038/s41598-019-51913-3
dc.identifier.urihttp://hdl.handle.net/10754/660133
dc.description.abstractInterleukin-1 receptor associated kinase 3 (IRAK3) is a cytoplasmic homeostatic mediator of inflammatory responses and is potentially useful as a prognostic marker in inflammation. IRAK3 inhibits signalling cascades downstream of myddosome complexes associated with toll like receptors. IRAK3 contains a death domain that interacts with other IRAK family members, a pseudokinase domain and a C-terminus domain involved with tumour necrosis factor receptor associated factor 6 (TRAF6). Previous bioinformatic studies revealed that IRAK3 contained a guanylate cyclase centre in its pseudokinase domain but its role in IRAK3 action is unresolved. We demonstrate that wildtype IRAK3 is capable of producing cGMP. Furthermore, we show that a specific point mutation in the guanylate cyclase centre reduced cGMP production. Cells containing toll like receptor 4 and a nuclear factor kappa-light-chain-enhancer of activated B cells (NFĸB) reporter system were transfected with IRAK3 or mutant IRAK3 proteins. Cell-permeable cGMP treatment of untransfected control cells suppresses downstream signalling through modulation of the NFĸB in the presence of lipopolysaccharides. Cells transfected with wildtype IRAK3 also suppress lipopolysaccharide induced NFĸB activity in the absence of exogenous cGMP. Lipopolysaccharide induced NFĸB activity was not suppressed in cells transfected with the IRAK3 mutant with reduced cGMP-generating capacity. Whereas in the presence of exogenously applied cell-permeable cGMP the IRAK3 mutant was able to retain its function by suppressing lipopolysaccharide induced NFĸB activity. Furthermore, increasing the amount of membrane permeable cGMP did not affect IRAK3's ability to reduce NFĸB activity. These results suggest that cGMP generated by IRAK3 may be involved in regulatory function of the protein where the presence of cGMP may selectively affect downstream signalling pathway(s) by modulating binding and/or activity of nearby proteins that interact in the inflammatory signalling cascade.
dc.description.sponsorshipSupport from the Australian Research Council’s Discovery funding scheme (project number DP110104164) and the Monash Institute of Pharmaceutical Science Large Grant Support Scheme is gratefully acknowledged. Research was sponsored by the Army Research Office and was accomplished under Grant Number W911NF-17-1-0303. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Army Research Office or the U.S. Government. LAF received a scholarship from the Monash Institute of Pharmaceutical Sciences. AW is supported by the National Natural Science Foundation of China (Grant no. 31850410470) and the Zhejiang Provincial Natural Science Foundation of China (Grant no. LQ19C130001).
dc.publisherSpringer Nature
dc.relation.urlhttp://www.nature.com/articles/s41598-019-51913-3
dc.relation.urlhttps://www.nature.com/articles/s41598-019-51913-3.pdf
dc.rightsThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleIRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity.
dc.typeArticle
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Division
dc.identifier.journalScientific reports
dc.eprint.versionPublisher's Version/PDF
dc.contributor.institutionMonash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
dc.contributor.institutionLa Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC, 3552, Australia.
dc.contributor.institutionAgriBio, La Trobe University, Bundoora, VIC, 3083, Australia J. I. Wheeler
dc.contributor.institutionDepartment of Biology, Wenzhou-Kean University, 88 Daxue Road, Ouhai, Wenzhou, Zhejiang Province, 325060, China A. Wong
kaust.personWong, Aloysius Tze
refterms.dateFOA2019-11-20T07:09:02Z


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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Except where otherwise noted, this item's license is described as This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.