PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Cells, Cultured
Fibroblasts
/ virology
HeLa Cells
Humans
Interferon Regulatory Factor-3
/ metabolism
Interferon-beta
/ metabolism
Mice
Mitochondrial Proteins
/ immunology
Phosphoprotein Phosphatases
/ immunology
Poly I-C
/ immunology
Protein Serine-Threonine Kinases
/ metabolism
Rhabdoviridae Infections
/ immunology
Signal Transduction
Vesicular stomatitis Indiana virus
/ immunology
Virus Replication
/ immunology
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 05 2020
20 05 2020
Historique:
received:
03
12
2019
accepted:
24
04
2020
entrez:
21
5
2020
pubmed:
21
5
2020
medline:
15
12
2020
Statut:
epublish
Résumé
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. IFNβ induces cellular antiviral defense mechanisms and thereby contributes to pathogen clearance. Accumulating evidence suggests that mitochondria constitute a crucial platform for the induction of antiviral immunity. Here we demonstrate that the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) is important for the antiviral cellular response. Following challenge of HeLa cells with the dsRNA-analog poly(I:C), PGAM5 oligomers and high levels of PGAM5 were found in mitochondrial aggregates. Using immunoprecipitation, a direct interaction of PGAM5 with the mitochondrial antiviral-signaling protein (MAVS) was demonstrated. In addition, PGAM5 deficient cells showed diminished expression of IFNβ and IFNβ target genes as compared to WT cells. Moreover, PGAM5 deficient mouse embryonic fibroblasts (MEFs) exhibited decreased phosphorylation levels of IRF3 and TBK1 when challenged with poly(I:C) intracellularly. Finally, PGAM5 deficient MEFs, upon infection with vesicular stomatitis virus (VSV), revealed diminished IFNβ expression and increased VSV replication. Collectively, our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection.
Identifiants
pubmed: 32433485
doi: 10.1038/s41598-020-65155-1
pii: 10.1038/s41598-020-65155-1
pmc: PMC7239892
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
IRF3 protein, human
0
Interferon Regulatory Factor-3
0
MAVS protein, human
0
Mitochondrial Proteins
0
Interferon-beta
77238-31-4
Protein Serine-Threonine Kinases
EC 2.7.11.1
TBK1 protein, human
EC 2.7.11.1
PGAM5 protein, human
EC 3.1.3.16
Phosphoprotein Phosphatases
EC 3.1.3.16
Poly I-C
O84C90HH2L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8323Références
Kawai, T. & Akira, S. Toll-like receptor and RIG-I-like receptor signaling. Annals of the New York Academy of Sciences 1143, 1–20, https://doi.org/10.1196/annals.1443.020 (2008).
doi: 10.1196/annals.1443.020
pubmed: 19076341
Wu, J. & Chen, Z. J. Innate immune sensing and signaling of cytosolic nucleic acids. Annual review of immunology 32, 461–488, https://doi.org/10.1146/annurev-immunol-032713-120156 (2014).
doi: 10.1146/annurev-immunol-032713-120156
pubmed: 24655297
Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature immunology 6, 981–988, https://doi.org/10.1038/ni1243 (2005).
doi: 10.1038/ni1243
pubmed: 16127453
Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172, https://doi.org/10.1038/nature04193 (2005).
doi: 10.1038/nature04193
pubmed: 16177806
Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682, https://doi.org/10.1016/j.cell.2005.08.012 (2005).
doi: 10.1016/j.cell.2005.08.012
pubmed: 16125763
Xu, L. G. et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Molecular cell 19, 727–740, https://doi.org/10.1016/j.molcel.2005.08.014 (2005).
doi: 10.1016/j.molcel.2005.08.014
pubmed: 16153868
Hou, F. et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146, 448–461, https://doi.org/10.1016/j.cell.2011.06.041 (2011).
doi: 10.1016/j.cell.2011.06.041
pubmed: 21782231
pmcid: 3179916
Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nature reviews. Immunology 16, 35–50, https://doi.org/10.1038/nri.2015.8 (2016).
doi: 10.1038/nri.2015.8
pubmed: 26711677
Holze, C. et al. Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. Nature immunology 19, 130–140, https://doi.org/10.1038/s41590-017-0013-y (2018).
doi: 10.1038/s41590-017-0013-y
pubmed: 29255269
Bernkopf, D. B. et al. Pgam5 released from damaged mitochondria induces mitochondrial biogenesis via Wnt signaling. The Journal of cell biology 217, 1383–1394, https://doi.org/10.1083/jcb.201708191 (2018).
doi: 10.1083/jcb.201708191
pubmed: 29438981
pmcid: 5881504
Rauschenberger, V. et al. The phosphatase Pgam5 antagonizes Wnt/beta-Catenin signaling in embryonic anterior-posterior axis patterning. Development 144, 2234–2247, https://doi.org/10.1242/dev.144477 (2017).
doi: 10.1242/dev.144477
pubmed: 28506997
Wang, Z., Jiang, H., Chen, S., Du, F. & Wang, X. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148, 228–243, https://doi.org/10.1016/j.cell.2011.11.030 (2012).
doi: 10.1016/j.cell.2011.11.030
pubmed: 22265414
Chen, G. et al. A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Molecular cell 54, 362–377, https://doi.org/10.1016/j.molcel.2014.02.034 (2014).
doi: 10.1016/j.molcel.2014.02.034
pubmed: 24746696
He, G. W. et al. PGAM5-mediated programmed necrosis of hepatocytes drives acute liver injury. Gut 66, 716–723, https://doi.org/10.1136/gutjnl-2015-311247 (2017).
doi: 10.1136/gutjnl-2015-311247
pubmed: 27566130
Moriwaki, K. et al. The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages. Journal of immunology 196, 407–415, https://doi.org/10.4049/jimmunol.1501662 (2016).
doi: 10.4049/jimmunol.1501662
Ma, K. et al. Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate. Cell Death Differ https://doi.org/10.1038/s41418-019-0396-4 (2019).
doi: 10.1038/s41418-019-0396-4
pubmed: 31853006
pmcid: 7206130
Kato, H. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205, 1601–1610, https://doi.org/10.1084/jem.20080091 (2008).
doi: 10.1084/jem.20080091
pubmed: 18591409
pmcid: 2442638
Marq, J. B., Hausmann, S., Veillard, N., Kolakofsky, D. & Garcin, D. Short double-stranded RNAs with an overhanging 5’ ppp-nucleotide, as found in arenavirus genomes, act as RIG-I decoys. J Biol Chem 286, 6108–6116, https://doi.org/10.1074/jbc.M110.186262 (2011).
doi: 10.1074/jbc.M110.186262
pubmed: 21159780
Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630, https://doi.org/10.1126/science.aaa2630 (2015).
doi: 10.1126/science.aaa2630
pubmed: 25636800
Ruiz, K. et al. Functional role of PGAM5 multimeric assemblies and their polymerization into filaments. Nat Commun 10, 531, https://doi.org/10.1038/s41467-019-08393-w (2019).
doi: 10.1038/s41467-019-08393-w
pubmed: 30705304
pmcid: 6355839
Wilkins, J. M., McConnell, C., Tipton, P. A. & Hannink, M. A conserved motif mediates both multimer formation and allosteric activation of phosphoglycerate mutase 5. J Biol Chem 289, 25137–25148, https://doi.org/10.1074/jbc.M114.565549 (2014).
doi: 10.1074/jbc.M114.565549
pubmed: 25012655
pmcid: 4155678
Park, Y. S., Choi, S. E. & Koh, H. C. PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. Toxicol Lett 284, 120–128, https://doi.org/10.1016/j.toxlet.2017.12.004 (2018).
doi: 10.1016/j.toxlet.2017.12.004
pubmed: 29241732
Blasius, A. L. & Beutler, B. Intracellular toll-like receptors. Immunity 32, 305–315, https://doi.org/10.1016/j.immuni.2010.03.012 (2010).
doi: 10.1016/j.immuni.2010.03.012
pubmed: 20346772
pmcid: 20346772
Schlee, M., Barchet, W., Hornung, V. & Hartmann, G. Beyond double-stranded RNA-type I IFN induction by 3pRNA and other viral nucleic acids. Curr Top Microbiol Immunol 316, 207–230, https://doi.org/10.1007/978-3-540-71329-6_11 (2007).
doi: 10.1007/978-3-540-71329-6_11
pubmed: 17969450
pmcid: 7120510
Crill, E. K., Furr-Rogers, S. R. & Marriott, I. RIG-I is required for VSV-induced cytokine production by murine glia and acts in combination with DAI to initiate responses to HSV-1. Glia 63, 2168–2180, https://doi.org/10.1002/glia.22883 (2015).
doi: 10.1002/glia.22883
pubmed: 26146945
pmcid: 4600648