UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis

Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of...

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Autores principales:	Hera Kim, Yashwanth Subbannayya, Fiachra Humphries, Astrid Skejsol, Sneha M. Pinto, Miriam Giambelluca, Terje Espevik, Katherine A. Fitzgerald, Richard K. Kandasamy
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/808160eb61c14cfaa9608bd6b662ea43
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spelling	oai:doaj.org-article:808160eb61c14cfaa9608bd6b662ea432021-11-04T06:49:42ZUMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis1932-6203https://doaj.org/article/808160eb61c14cfaa9608bd6b662ea432021-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550426/?tool=EBIhttps://doaj.org/toc/1932-6203Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of interferon regulatory factors (IRFs), which subsequently leads to type I interferon (IFN) response. In the current study, we sought to expand the scope of gene expression changes in THP1-derived macrophages upon TLR4 activation and to identify interferon-stimulated genes. RNA-seq analysis led to the identification of several known and novel differentially expressed genes, including CMPK2, particularly in association with type I IFN signaling. We performed an in-depth characterization of CMPK2 expression, a nucleoside monophosphate kinase that supplies intracellular UTP/CTP for nucleic acid synthesis in response to type I IFN signaling in macrophages. CMPK2 was significantly induced at both RNA and protein levels upon stimulation with TLR4 ligand—LPS and TLR3 ligand—Poly (I:C). Confocal microscopy and subcellular fractionation indicated CMPK2 localization in both cytoplasm and mitochondria of THP-1 macrophages. Furthermore, neutralizing antibody-based inhibition of IFNAR receptor in THP-1 cells and BMDMs derived from IFNAR KO and IRF3 KO knockout mice further revealed that CMPK2 expression is dependent on LPS/Poly (I:C) mediated IRF3- type I interferon signaling. In summary, our findings suggest that CMPK2 is a potential interferon-stimulated gene in THP-1 macrophages and that CMPK2 may facilitate IRF3- type I IFN-dependent anti-bacterial and anti-viral roles.Hera KimYashwanth SubbannayyaFiachra HumphriesAstrid SkejsolSneha M. PintoMiriam GiambellucaTerje EspevikKatherine A. FitzgeraldRichard K. KandasamyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hera Kim Yashwanth Subbannayya Fiachra Humphries Astrid Skejsol Sneha M. Pinto Miriam Giambelluca Terje Espevik Katherine A. Fitzgerald Richard K. Kandasamy UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis
description	Toll-like receptors (TLRs) are highly-conserved pattern recognition receptors that mediate innate immune responses to invading pathogens and endogenous danger signals released from damaged and dying cells. Activation of TLRs trigger downstream signaling cascades, that culminate in the activation of interferon regulatory factors (IRFs), which subsequently leads to type I interferon (IFN) response. In the current study, we sought to expand the scope of gene expression changes in THP1-derived macrophages upon TLR4 activation and to identify interferon-stimulated genes. RNA-seq analysis led to the identification of several known and novel differentially expressed genes, including CMPK2, particularly in association with type I IFN signaling. We performed an in-depth characterization of CMPK2 expression, a nucleoside monophosphate kinase that supplies intracellular UTP/CTP for nucleic acid synthesis in response to type I IFN signaling in macrophages. CMPK2 was significantly induced at both RNA and protein levels upon stimulation with TLR4 ligand—LPS and TLR3 ligand—Poly (I:C). Confocal microscopy and subcellular fractionation indicated CMPK2 localization in both cytoplasm and mitochondria of THP-1 macrophages. Furthermore, neutralizing antibody-based inhibition of IFNAR receptor in THP-1 cells and BMDMs derived from IFNAR KO and IRF3 KO knockout mice further revealed that CMPK2 expression is dependent on LPS/Poly (I:C) mediated IRF3- type I interferon signaling. In summary, our findings suggest that CMPK2 is a potential interferon-stimulated gene in THP-1 macrophages and that CMPK2 may facilitate IRF3- type I IFN-dependent anti-bacterial and anti-viral roles.
format	article
author	Hera Kim Yashwanth Subbannayya Fiachra Humphries Astrid Skejsol Sneha M. Pinto Miriam Giambelluca Terje Espevik Katherine A. Fitzgerald Richard K. Kandasamy
author_facet	Hera Kim Yashwanth Subbannayya Fiachra Humphries Astrid Skejsol Sneha M. Pinto Miriam Giambelluca Terje Espevik Katherine A. Fitzgerald Richard K. Kandasamy
author_sort	Hera Kim
title	UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis
title_short	UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis
title_full	UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis
title_fullStr	UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis
title_full_unstemmed	UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis
title_sort	ump-cmp kinase 2 gene expression in macrophages is dependent on the irf3-ifnar signaling axis
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/808160eb61c14cfaa9608bd6b662ea43
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UMP-CMP kinase 2 gene expression in macrophages is dependent on the IRF3-IFNAR signaling axis

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