IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 Jan 2024
02 Jan 2024
Historique:
received:
07
03
2023
accepted:
11
12
2023
medline:
4
1
2024
pubmed:
4
1
2024
entrez:
3
1
2024
Statut:
epublish
Résumé
TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.
Identifiants
pubmed: 38167258
doi: 10.1038/s41467-023-44372-y
pii: 10.1038/s41467-023-44372-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
130Subventions
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 787826
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 414786233
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 390661388
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 413326622
Informations de copyright
© 2024. The Author(s).
Références
Crow, Y. J. & Stetson, D. B. The type I interferonopathies: 10 years on. Nat. Rev. Immunol. 22, 471–483 (2022).
pubmed: 34671122
doi: 10.1038/s41577-021-00633-9
Hemmi, H. et al. The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. 199, 1641–1650 (2004).
pubmed: 15210742
pmcid: 2212809
doi: 10.1084/jem.20040520
Kagan, J. C. et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat. Immunol. 9, 361–368 (2008).
pubmed: 18297073
pmcid: 4112825
doi: 10.1038/ni1569
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 (2005).
pubmed: 16125763
doi: 10.1016/j.cell.2005.08.012
Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).
pubmed: 12855817
doi: 10.1126/science.1087262
Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 4, 1144–1150 (2003).
pubmed: 14556004
doi: 10.1038/ni986
Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5, 730–737 (2004).
pubmed: 15208624
doi: 10.1038/ni1087
Zeng, W. et al. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141, 315–330 (2010).
pubmed: 20403326
pmcid: 2919214
doi: 10.1016/j.cell.2010.03.029
Zhang, C. et al. Structural basis of STING binding with and phosphorylation by TBK1. Nature 567, 394–398 (2019).
pubmed: 30842653
pmcid: 6862768
doi: 10.1038/s41586-019-1000-2
Zhao, B. et al. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature 569, 718–722 (2019).
pubmed: 31118511
pmcid: 6596994
doi: 10.1038/s41586-019-1228-x
Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).
pubmed: 25636800
doi: 10.1126/science.aaa2630
Lin, R., Heylbroeck, C., Pitha, P. M. & Hiscott, J. Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol. Cell Biol. 18, 2986–2996 (1998).
pubmed: 9566918
pmcid: 110678
doi: 10.1128/MCB.18.5.2986
Yoneyama, M. et al. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J. 17, 1087–1095 (1998).
pubmed: 9463386
pmcid: 1170457
doi: 10.1093/emboj/17.4.1087
Fitzgerald, K. A. et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491–496 (2003).
pubmed: 12692549
doi: 10.1038/ni921
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).
pubmed: 12887920
doi: 10.1016/S0092-8674(03)00521-X
Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).
pubmed: 25592536
doi: 10.1038/nature14191
Wang, L., Du, F. & Wang, X. TNF-alpha induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).
pubmed: 18485876
doi: 10.1016/j.cell.2008.03.036
Polykratis, A. et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J. Immunol. 193, 1539–1543 (2014).
pubmed: 25015821
doi: 10.4049/jimmunol.1400590
Dondelinger, Y. et al. NF-kappaB-independent role of IKKalpha/IKKbeta in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 63–76 (2015).
pubmed: 26344099
doi: 10.1016/j.molcel.2015.07.032
Dondelinger, Y. et al. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat. Commun. 10, 1729 (2019).
pubmed: 30988283
pmcid: 6465317
doi: 10.1038/s41467-019-09690-0
Menon, M. B. et al. p38(MAPK)/MK2-dependent phosphorylation controls cytotoxic RIPK1 signalling in inflammation and infection. Nat. Cell Biol. 19, 1248–1259 (2017).
pubmed: 28920954
doi: 10.1038/ncb3614
Jaco, I. et al. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol. Cell 66, 698–710 e695 (2017).
pubmed: 28506461
pmcid: 5459754
doi: 10.1016/j.molcel.2017.05.003
Dondelinger, Y. et al. MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat. Cell Biol. 19, 1237–1247 (2017).
pubmed: 28920952
doi: 10.1038/ncb3608
Bonnard, M. et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J. 19, 4976–4985 (2000).
pubmed: 10990461
pmcid: 314216
doi: 10.1093/emboj/19.18.4976
Matsui, K. et al. Cutting edge: role of TANK-binding kinase 1 and inducible IkappaB kinase in IFN responses against viruses in innate immune cells. J. Immunol. 177, 5785–5789 (2006).
pubmed: 17056502
doi: 10.4049/jimmunol.177.9.5785
Xu, D. et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell 174, 1477–1491 e1419 (2018).
pubmed: 30146158
pmcid: 6128749
doi: 10.1016/j.cell.2018.07.041
Taft, J. et al. Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 184, 4447–4463 e4420 (2021).
pubmed: 34363755
pmcid: 8380741
doi: 10.1016/j.cell.2021.07.026
Lafont, E. et al. TBK1 and IKKepsilon prevent TNF-induced cell death by RIPK1 phosphorylation. Nat. Cell Biol. 20, 1389–1399 (2018).
pubmed: 30420664
pmcid: 6268100
doi: 10.1038/s41556-018-0229-6
Jin, J. et al. The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-kappaB signaling. Nat. Immunol. 13, 1101–1109 (2012).
pubmed: 23023393
pmcid: 3477307
doi: 10.1038/ni.2423
Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995).
pubmed: 8559668
pmcid: 307516
doi: 10.1093/nar/23.24.5080
Gao, T. et al. Myeloid cell TBK1 restricts inflammatory responses. Proc. Natl Acad. Sci. USA 119, e2107742119 (2022).
pubmed: 35074921
pmcid: 8794809
doi: 10.1073/pnas.2107742119
Clark, K., Plater, L., Peggie, M. & Cohen, P. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J. Biol. Chem. 284, 14136–14146 (2009).
pubmed: 19307177
pmcid: 2682862
doi: 10.1074/jbc.M109.000414
Bain, J. et al. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 408, 297–315 (2007).
pubmed: 17850214
pmcid: 2267365
doi: 10.1042/BJ20070797
Clark, K. et al. Novel cross-talk within the IKK family controls innate immunity. Biochem. J. 434, 93–104 (2011).
pubmed: 21138416
doi: 10.1042/BJ20101701
Takahashi, N. et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 3, e437 (2012).
pubmed: 23190609
pmcid: 3542611
doi: 10.1038/cddis.2012.176
Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
pubmed: 28151659
doi: 10.1021/acs.jmedchem.6b01751
Pietras, E. M. et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat. Cell Biol. 18, 607–618 (2016).
pubmed: 27111842
pmcid: 4884136
doi: 10.1038/ncb3346
Ogura, T. et al. Interleukin-18 stimulates hematopoietic cytokine and growth factor formation and augments circulating granulocytes in mice. Blood 98, 2101–2107 (2001).
pubmed: 11567996
doi: 10.1182/blood.V98.7.2101
Kim, J. et al. IL-33-induced hematopoietic stem and progenitor cell mobilization depends upon CCR2. J. Immunol. 193, 3792–3802 (2014).
pubmed: 25143444
doi: 10.4049/jimmunol.1400176
Kuai, J. et al. NAK is recruited to the TNFR1 complex in a TNFalpha-dependent manner and mediates the production of RANTES: identification of endogenous TNFR-interacting proteins by a proteomic approach. J. Biol. Chem. 279, 53266–53271 (2004).
pubmed: 15485837
doi: 10.1074/jbc.M411037200
Heo, J. M., Ordureau, A., Paulo, J. A., Rinehart, J. & Harper, J. W. The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol. Cell 60, 7–20 (2015).
pubmed: 26365381
pmcid: 4592482
doi: 10.1016/j.molcel.2015.08.016
Zhao, P. et al. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue. Cell 172, 731–743 e712 (2018).
pubmed: 29425491
pmcid: 5808582
doi: 10.1016/j.cell.2018.01.007
Rauch, J., Volinsky, N., Romano, D. & Kolch, W. The secret life of kinases: functions beyond catalysis. Cell Commun. Signal 9, 23 (2011).
pubmed: 22035226
pmcid: 3215182
doi: 10.1186/1478-811X-9-23
Jouan-Lanhouet, S. et al. TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation. Cell Death Differ. 19, 2003–2014 (2012).
pubmed: 22814620
pmcid: 3504714
doi: 10.1038/cdd.2012.90
Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000).
pubmed: 11101870
doi: 10.1038/82732
Kumari, S. et al. Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice. Immunity 39, 899–911 (2013).
pubmed: 24211183
doi: 10.1016/j.immuni.2013.10.009
Kumari, S. et al. NF-kappaB inhibition in keratinocytes causes RIPK1-mediated necroptosis and skin inflammation. Life Sci Alliance 4, (2021).
Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).
pubmed: 12075355
doi: 10.1038/nature00820
Kondylis, V. et al. NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. Cancer Cell 28, 582–598 (2015).
pubmed: 26555174
pmcid: 4644221
doi: 10.1016/j.ccell.2015.10.001
Ehlken, H. et al. Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell Death Differ. 21, 1721–1732 (2014).
pubmed: 24971483
pmcid: 4211370
doi: 10.1038/cdd.2014.83
Luedde, T. et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007).
pubmed: 17292824
doi: 10.1016/j.ccr.2006.12.016
Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).
pubmed: 17361131
doi: 10.1038/nature05698
Vlantis, K. et al. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-kappaB-dependent and -independent functions. Immunity 44, 553–567 (2016).
pubmed: 26982364
pmcid: 4803910
doi: 10.1016/j.immuni.2016.02.020
Heinz, L. X. et al. TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature 581, 316–322 (2020).
pubmed: 32433612
pmcid: 7610944
doi: 10.1038/s41586-020-2282-0
Lazarou, M. et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524, 309–314 (2015).
pubmed: 26266977
pmcid: 5018156
doi: 10.1038/nature14893
Richter, B. et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc. Natl Acad. Sci. USA 113, 4039–4044 (2016).
pubmed: 27035970
pmcid: 4839414
doi: 10.1073/pnas.1523926113
Matsumoto, G., Shimogori, T., Hattori, N. & Nukina, N. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation. Hum. Mol. Genet. 24, 4429–4442 (2015).
pubmed: 25972374
doi: 10.1093/hmg/ddv179
Luedde, T. et al. IKK1 and IKK2 cooperate to maintain bile duct integrity in the liver. Proc. Natl Acad. Sci. USA 105, 9733–9738 (2008).
pubmed: 18606991
pmcid: 2474544
doi: 10.1073/pnas.0800198105
Madison, B. B. et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002).
pubmed: 12065599
doi: 10.1074/jbc.M204935200
Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).
pubmed: 23273845
doi: 10.1016/j.immuni.2012.12.001
Kellendonk, C., Opherk, C., Anlag, K., Schutz, G. & Tronche, F. Hepatocyte-specific expression of Cre recombinase. Genesis 26, 151–153 (2000).
pubmed: 10686615
doi: 10.1002/(SICI)1526-968X(200002)26:2<151::AID-GENE17>3.0.CO;2-E
Hafner, M. et al. Keratin 14 Cre transgenic mice authenticate keratin 14 as an oocyte-expressed protein. Genesis 38, 176–181 (2004).
pubmed: 15083518
doi: 10.1002/gene.20016
Schwarzer, R., Jiao, H., Wachsmuth, L., Tresch, A. & Pasparakis, M. FADD and caspase-8 regulate gut homeostasis and inflammation by controlling MLKL- and GSDMD-mediated death of intestinal epithelial cells. Immunity 52, 978–993 e976 (2020).
pubmed: 32362323
doi: 10.1016/j.immuni.2020.04.002