Abstract
NF-κB (nuclear factor κB) has a pivotal role in many cellular processes, including the inflammatory and immune responses and, therefore, its activation is tightly regulated by the IKK (IκB kinase) complex and by IκBα degradation. When Shigella bacteria multiply within epithelial cells they release peptidoglycans, which are recognized by Nod1 and stimulate the NF-κB pathway, thus leading to a severe inflammatory response. Here, we show that IpaH9.8, a Shigella effector possessing E3 ligase activity, dampens the NF-κB-mediated inflammatory response to the bacterial infection in a unique way. IpaH9.8 interacts with NEMO/IKKγ and ABIN-1, a ubiquitin-binding adaptor protein, promoting ABIN-1-dependent polyubiquitylation of NEMO. Consequently, polyubiquitylated NEMO undergoes proteasome-dependent degradation, which perturbs NF-κB activation. As NEMO is essential for NF-κB activation, we propose that the polyubiquitylation and degradation of NEMO during Shigella infection is a new bacterial strategy to modulate host inflammatory responses.
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References
Akira, S., Uematsu, S., & Takeuchi, O. Pathogen recognition and innate immunity. Cell. 124, 783–801 (2006).
Martnon, F, Mayor, A & Tchopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).
Vance, R. E, Isberg, R. R & Portnoy, D. A. Patterns of pathogenesis: discrimination of pathogenic and nonpathogenic microbes by the innate immune system. Cell Host Microbe. 6, 10–21 (2009).
Li, Q. T. & Verma, L. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002).
Sebban, H., Yamaoka, S. & Courtois, G. Posttranslational modifications of NEMO and its partners in NF-κB signaling. Trends in Cell Biol. 16, 569–577 (2006).
Chen, Z. J. Ubiquitin signalling in the NF-κB pathway. Nature Cell. Biol. 7, 758–766 (2005).
Fritz, J. H., Ferrero, R. L., Philipott, D. J & Girardin, S. E. Nod-like proteins in immunity, inflammation and disease. Nature Immunol. 7, 1250–1257 (2006).
Sansonetti, P. J & Di Santo, J. P. Debugging how bacteria manipulate the immune response. Immunity. 26, 149–161 (2007).
Bhavsar, A. P., Guttman, J. A. & Finlay, B. B. Manipulation of host-cell pathways by bacterial pathogens. Nature. 449, 827–834 (2007).
Kim, D. W. et al. The Shigella flexneri effector OspG interferes with innate immune responses by targeting ubiquitin-conjugating enzymes. Proc. Natl Acad. Sci. USA. 102, 14046–14051 (2005).
Arbibe, L. et al. An injected bacterial effector targets chromatin access for transcription factor NF-κB to alter transcription of host genes involved in immune responses. Nature Immunol. 8, 47–56 (2007).
Okuda, J. et al. Shigella effector IpaH9.8 binds to a splicing factor U2AF35 to modulate host immune responses. Biochem. Biophys. Res. Commun. 333, 531–539 (2005).
Ogawa, M., Handa, Y., Ashida, H., Suzuki, M. & Sawakawa, C. The versatility of Shigella effectors. Nature Rev. Micro. 6, 1–7 (2008).
Ashida, H., Toyotome, T., Nagai, T. & Sasakawa, C. Shigella chromosomal IpaH proteins are secreted via the type III secretion system and act as effectors. Mol. Microbiol. 63, 680–693 (2007).
Rohde, J. R., Breitkreutz, A., Chenal, A., Sansonetti, P. J. & Parsot, C. Type III secretion effectors of the IpaH family are E3 ubiquitin ligase. Cell Host Microbe 1, 77–83 (2007).
Singer, A. U. et al. Structure of the Shigella T3SS effector IpaH defines a new class of E3 ubiquitin ligases. Nature Struct. Mol.Biol. 15, 1293–1301 (2008).
Zhu, Y. et al. Structure of a Shigella effector reveals a new class of ubiquitin ligases. Nature Struct. Mol. Biol. 15, 1302–1308 (2008).
Miller, S. I. A Salmonella enterica serovar typhimurium translocated leucine-rich repeat effector protein inhibits NF-κ B-dependent gene expression. Infect. Immun. 71, 4052–4058 (2003).
Mauro, C. et al. ABIN-1 binds to NEMO/IKKγ and co-operates with A20 in inhibiting NF-κB. J. Biol. Chem. 281, 18482–18488 (2006).
Heyninck, K. et al. The zinc finger protein A20 inhibits TNF-induced NF-κB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-κB-inhibiting protein ABIN. J. Cell Biol. 145, 1471–1482 (1999).
Heyninck, K., Kreike, M. M. & Beyaert, R. Structure-function analysis of the A20-binding inhibitor of NF-kappa B activation, ABIN-1. FEBS Lett. 536, 135–140 (2003).
Dikic, I. Ubiquitylation and cell signaling. EMBO J. 24, 3353–3359 (2005).
Zhou, H. et al. Bcl10 activates the NF-κB pathway through ubiquitination of NEMO. Nature. 427, 167–171 (2004).
Sun, L., Deng, L., Ea C. K., Xia, Z. P. & Chen, Z. J. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell. 14, 289–301 (2004).
Abbott, D. W., Wilkins, A., Asara, J. & Cantley, L. C. The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr. Biol. 14, 2217–2227 (2004).
Abbott, D. W. et al. Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol. Cell. Biol. 27, 6012–6025 (2007).
Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nature Cell Biol. 11, 123–132 (2009).
Schmidt-Supprian, M. et al. NEMO/IKKγ-deficient mice model incontinemtia pigmenti. Mol. Cell 5, 981–992 (2000).
Wagner, S. et al. Ubiquitin binding mediates the NF-κB inhibitory potential of ABIN proteins. Oncogene 21, 1–7 (2008).
Ohshima, S. et al. ABIN-1 is a ubiquitin sensor that restricts cell death and sustain embryonic development. Nature 457, 906–909 (2009).
Komander, D. et al. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep. 10, 466–473 (2009).
Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136, 1098–1109 (2009).
Toyotome, T. et al. Shigella protein IpaH(9.8) is secreted from bacteria within mammalian cells and transported to the nucleus. J. Biol. Chem. 276, 32071–32079 (2001).
Kim, M., Tezuka, T., Tanaka, K. & Yamamoto, T. Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene. 23, 1645–1655 (2004).
Acknowledgements
We thank the members of the Sasakawa laboratory for their advice. This work was supported by Grand-in-Aid for Scientific Research (S) (20229006); a Grand-in-Aid for Exploratory Research (20659067); a Grant-in-Aid for Scientific Research on Priority Areas (18073003); the Strategic Cooperation to Control Emerging and Reemerging Infections Funded by The Special Coordination Funds for Promoting Science and Technology; and a Contract Research Fund for the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST).
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H.A. designed and performed the experiments. M.K. gave advice and designed the experiments. M.S.-S. provided NEMO materials. A.M. provided ABIN-1 materials. M.O. gave advice. C.S. conceived and wrote the paper.
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Ashida, H., Kim, M., Schmidt-Supprian, M. et al. A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKγ to dampen the host NF-κB-mediated inflammatory response. Nat Cell Biol 12, 66–73 (2010). https://doi.org/10.1038/ncb2006
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DOI: https://doi.org/10.1038/ncb2006
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