Abstract
Ubiquitylation is a versatile post-translational modification. Met1-linked linear ubiquitin chains are involved in nuclear factor-κB signalling and cell death, and dysfunctions in linear ubiquitylation underlie chronic inflammation. Recent identification of deubiquitylating enzymes and binding domains that are specific for linear ubiquitin chains suggests new physiological roles for linear ubiquitin chains. Moreover, the ligase required for linear ubiquitylation has a crucial role in the pathogenesis of some malignancies. Structural and functional analyses of the conjugation and deconjugation of linear ubiquitin chains have enabled the development of new probes to study the roles of linear chain ubiquitylation.
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References
Deshaies, R. J. & Joazeiro, C. A. RING domain E3 ubiquitin ligases. Annu. Rev. Biochem. 78, 399–434 (2009).
Ikeda, F., Crosetto, N. & Dikic, I. What determines the specificity and outcomes of ubiquitin signaling? Cell 143, 677–681 (2010).
Berndsen, C. E. & Wolberger, C. New insights into ubiquitin E3 ligase mechanism. Nature Struct. Mol. Biol. 21, 301–307 (2014).
Komander, D., Clague, M. J. & Urbe, S. Breaking the chains: structure and function of the deubiquitinases. Nature Rev. Mol. Cell. Biol. 10, 550–563 (2009).
Iwai, K. & Tokunaga, F. Linear polyubiquitination: a new regulator of NF-κB activation. EMBO Rep. 10, 706–713 (2009).
Kirisako, T. et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 25, 4877–4887 (2006).
Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).
Tokunaga, F. et al. Involvement of linear polyubiquitylation of NEMO in NF-κB activation. Nature Cell Biol. 11, 123–132 (2009).
Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).
Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471, 637–641 (2011).
Lo, Y. C. et al. Structural basis for recognition of diubiquitins by NEMO. Mol. Cell 33, 602–615 (2009).
Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136, 1098–1109 (2009).
Keusekotten, K. et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153, 1312–1326 (2013).
Rieser, E., Cordier, S. M. & Walczak, H. Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem. Sci. 38, 94–102 (2013).
Sato, Y. et al. Specific recognition of linear ubiquitin chains by the Npl4 zinc finger (NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex. Proc. Natl Acad. Sci. USA 108, 20520–20525 (2011).
Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228–233 (2011).
Dubois, S. M. et al. A catalytic-independent role for the LUBAC in NF-κB activation upon antigen receptor engagement and in lymphoma cells. Blood 123, 2199–2203 (2014).
Yang, Y. et al. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discov. 4, 480–493 (2014).
Muller-Rischart, A. K. et al. The E3 ligase parkin maintains mitochondrial integrity by increasing linear ubiquitination of NEMO. Mol. Cell 49, 908–921 (2013).
Berger, S. B. et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. http://dx.doi.org/10.4049/jimmunol.1400499 (2014).
Iwai, K. Diverse ubiquitin signaling in NF-κB activation. Trends Cell Biol. 22, 355–364 (2012).
Stieglitz, B., Morris-Davies, A. C., Koliopoulos, M. G., Christodoulou, E. & Rittinger, K. LUBAC synthesizes linear ubiquitin chains via a thioester intermediate. EMBO Rep. 13, 840–846 (2012).
Smit, J. J. et al. The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. EMBO J. 31, 3833–3844 (2012).
Yagi, H. et al. A non-canonical UBA-UBL interaction forms the linear-ubiquitin-chain assembly complex. EMBO Rep. 13, 462–468 (2012).
Tokunaga, F. et al. SHARPIN is a component of the NF-κB-activating linear ubiquitin chain assembly complex. Nature 471, 633–636 (2011).
Wenzel, D. M., Lissounov, A., Brzovic, P. S. & Klevit, R. E. UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids. Nature 474, 105–108 (2011).
Stieglitz, B. et al. Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 503, 422–426 (2013).
Fujita, H. et al. Mechanism underlying IκB kinase activation mediated by the linear ubiquitin chain assembly complex. Mol. Cell Biol. 34, 1322–1335 (2014).
Smit, J. J. et al. Target specificity of the E3 ligase LUBAC for ubiquitin and NEMO relies on different minimal requirements. J. Biol. Chem. 288, 31728–31737 (2013).
Rantala, J. K. et al. SHARPIN is an endogenous inhibitor of β1-integrin activation. Nature Cell Biol. 13, 1315–1324 (2011).
Rivkin, E. et al. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature 498, 318–324 (2013).
Komander, D. et al. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep. 10, 466–473 (2009).
Sun, S. C. CYLD: a tumor suppressor deubiquitinase regulating NF-κB activation and diverse biological processes. Cell Death Differ. 17, 25–34 (2010).
Harhaj, E. W. & Dixit, V. M. Regulation of NF-κB by deubiquitinases. Immunol. Rev. 246, 107–124 (2012).
Hymowitz, S. G. & Wertz, I. E. A20: from ubiquitin editing to tumour suppression. Nature Rev. Cancer 10, 332–341 (2010).
Verhelst, K. et al. A20 inhibits LUBAC-mediated NF-κB activation by binding linear polyubiquitin chains via its zinc finger 7. EMBO J. 31, 3845–3855 (2012).
Tokunaga, F. et al. Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation. EMBO J. 31, 3856–3870 (2012).
Skaug, B. et al. Direct, noncatalytic mechanism of IKK inhibition by A20. Mol. Cell 44, 559–571 (2011).
Elliott, P. R. et al. Molecular basis and regulation of OTULIN–LUBAC interaction. Mol. Cell 54, 335–348 (2014).
Schaeffer, V. et al. Binding of OTULIN to the PUB Domain of HOIP Controls NF-κB Signaling. Mol. Cell 54, 349–361 (2014).
Takiuchi, T. et al. Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. Genes Cells 19, 254–272 (2014).
Sowa, M. E., Bennett, E. J., Gygi, S. P. & Harper, J. W. Defining the human deubiquitinating enzyme interaction landscape. Cell 138, 389–403 (2009).
Yeung, H. O. et al. Insights into adaptor binding to the AAA protein p97. Biochem. Soc. Trans. 36, 62–67 (2008).
Emmerich, C. H. et al. Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. Proc. Natl Acad. Sci. USA 110, 15247–15252 (2013).
Fiil, B. K. et al. OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol. Cell 50, 818–830 (2013).
Hayden, M. S. & Ghosh, S. Shared principles in NF-κB signaling. Cell 132, 344–362 (2008).
Chen, Z. J. Ubiquitination in signaling to and activation of IKK. Immunol. Rev. 246, 95–106 (2012).
Sasaki, Y. et al. Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. EMBO J. 32, 2463–2476 (2013).
Xu, M., Skaug, B., Zeng, W. & Chen, Z. J. A ubiquitin replacement strategy in human cells reveals distinct mechanisms of IKK activation by TNFα and IL-1β. Mol. Cell 36, 302–314 (2009).
Xu, G. et al. Crystal structure of inhibitor of κB kinase β. Nature 472, 325–330 (2011).
Polley, S. et al. A structural basis for IκB kinase 2 activation via oligomerization-dependent trans auto-phosphorylation. PLoS Biol. 11, e1001581 (2013).
Clark, K., Nanda, S. & Cohen, P. Molecular control of the NEMO family of ubiquitin-binding proteins. Nature Rev. Mol. Cell Biol. 14, 673–685 (2013).
Haas, T. L. et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol. Cell 36, 831–844 (2009).
Inn, K. S. et al. Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. Mol. Cell 41, 354–365 (2011).
Niu, J., Shi, Y., Iwai, K. & Wu, Z. H. LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. EMBO J. 30, 3741–3753 (2011).
Belgnaoui, S. M. et al. Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS–TRAF3 complex. Cell Host Microbe 12, 211–222 (2012).
Damgaard, R. B. et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol. Cell 46, 746–758 (2012).
Gantke, T. Sriskantharajah, S., Sadowski, M. & Ley, S. C. IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunol. Rev. 246, 168–182 (2012).
Roget, K. et al. IKK2 regulates TPL-2 activation of ERK-1/2 MAP kinases by direct phosphorylation of TPL-2 serine 400. Mol. Cell Biol. 32, 4684–4690 (2012).
Kaiser, W. J. et al. RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471, 368–372 (2011).
Green, D. R., Oberst, A., Dillon, C. P., Weinlich, R. & Salvesen, G. S. RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol. Cell 44, 9–16 (2011).
Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).
Christofferson, D. E., Li, Y. & Yuan, J. Control of life-or-death decisions by RIP1 kinase. Annu. Rev. Physiol. 76, 129–150 (2014).
Tamiya, H. et al. IFN-γ or IFN-α ameliorates chronic proliferative dermatitis by inducing expression of linear ubiquitin chain assembly complex. J. Immunol. 192, 3793–3804 (2014).
Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nature Immunol. 13, 1178–1186 (2012).
Nilsson, J. et al. Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Ann. Neurol. 74, 914–919 (2013).
Kato, M. et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 459, 712–716 (2009).
Mackay, C. et al. E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. Cancer Res. 74, 2246–2257 (2014).
Tomonaga, M. et al. Activation of nuclear factor-κ B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells. Int. J. Oncol. 40, 409–417 (2012).
van Wijk, S. J. et al. Fluorescence-based sensors to monitor localization and functions of linear and K63-linked ubiquitin chains in cells. Mol. Cell 47, 797–809 (2012).
Wickliffe, K. E., Williamson, A., Meyer, H. J., Kelly, A. & Rape, M. K11-linked ubiquitin chains as novel regulators of cell division. Trends Cell Biol. 21, 656–663 (2011).
Acknowledgements
The authors are grateful to members of the Iwai laboratory for valuable discussions and insightful comments. The authors apologize to colleagues whose work could not be cited owing to space limitations. Work in the Iwai laboratory is partly supported by the Targeted Proteins Research Program (TPRP), the Project for Development of Innovative Research on Cancer Therapeutics, and by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant Numbers 22249008, 24112002 and 25253019).
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Iwai, K., Fujita, H. & Sasaki, Y. Linear ubiquitin chains: NF-κB signalling, cell death and beyond. Nat Rev Mol Cell Biol 15, 503–508 (2014). https://doi.org/10.1038/nrm3836
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DOI: https://doi.org/10.1038/nrm3836
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