In this paper Christoph Emmerich and Sam Strickson in Philip Cohen's lab have made several surprising findings about the structure and formation of the polyubiquitin chains that control the protein kinases that switch on the transcription factor NF-Ã_ºB. Their findings, reported in the latest issue of Proceedings of the National Academy of Sciences of the USA, may have important implications for the regulation of other biological processes.
NF-Ã_ºB plays a central role in the regulation of the immune system and other biological processes, such as the response to DNA damage. It is one of the most studied of all transcription factors, with entire scientific meetings being devoted to discussions about how it is regulated and how it controls cellular processes. The activation of NFÃ_ºB is catalyzed by the canonical IÃ_ºB kinase (IKK) complex, which comprises the protein kinases IKKÃ_± and IKKÃ_Â_ and a regulatory subunit called NEMO. Protein ubiquitylation and protein phosphorylation events are known to be needed for the IKK complex to be activated: Met1-linked (or linear) polyubiquitin chains have to bind to NEMO, and the activation loops of IKKÃ_± and IKKÃ_Â_ have to become phosphorylated by the protein kinase TAK1. Intriguingly, the activation of TAK1 itself requires the binding of Lys63-linked ubiquitin chains to its regulatory subunits TAB2 and TAB3.
There has been an intense debate about the relative roles and importance of Lys63-linked versus Met1-linked ubiquitin chains in the activation of the canonical IKK complex by inflammatory stimuli. Now Christoph Emmerich has introduced a new twist to this story by discovering that the TAK1-dependent activation of the IKK complex requires a new type of ubiquitin chain in which Met1-linked and Lys63-linked ubiquitin oligomers are attached covalently to one another as 'hybrid' ubiquitin chains. In the same paper Sam Strickson found that the formation of Lys63-linked ubiquitin chains is a pre-requisite for the formation of Met1-linked ubiquitin chains, since Met1-linked ubiquitin chains were not formed in response to interleukin-1 in cells lacking Ubc13, the E2 conjugating enzyme that specifies the formation of Lys63-linked ubiquitin chains. The authors point out that forming Lys63/Met1-linked hybrids makes more physiological sense than producing two different ubiquitin chains, because it enables the co-localisation of the canonical IKK complex and the TAK1 complex to the same polyubiquitin chain, which may facilitate the activation of the canonical IKK complex by TAK1.
The new paper also establishes that LUBAC (the Linear UBiquitin Assembly Complex) is the only E3 ligase that forms Met1-linked ubiquitin chains in response to IL-1, that HOIP is the catalytic subunit of LUBAC and that Met1-linked ubiquitin chains are required to increase the efficiency with which the canonical IKK complex is activated.
Although the paper will help to resolve the debate about the relative roles of Lys63-linked and Met1-linked ubiquitin chains in the activation of NFÃ_ºB, it also raises many interesting new questions. For example, are the Lys63/Met1-linked ubiquitin hybrids formed in response to IL-1 also produced during the activation of other cellular processes? What is the precise topology of the ubiquitin oligomers in the hybrid molecules and what length do they need to be to activate NEMO-dependent processes efficiently? Do these ubiquitin chains need to be attached covalently to other proteins to control cellular events or are ubiquitin chains that are not anchored to any other protein sufficient for activation? What other proteins does NEMO interact with in an ubiquitin-dependent manner and what are their functions? What other protein kinases besides TAK1 are needed for the activation of the canonical IKK complex by signals other than IL-1? The answers to these and other questions will undoubtedly emerge from research performed in the years to come.
NF-Ã_ºB plays a central role in the regulation of the immune system and other biological processes, such as the response to DNA damage. It is one of the most studied of all transcription factors, with entire scientific meetings being devoted to discussions about how it is regulated and how it controls cellular processes. The activation of NFÃ_ºB is catalyzed by the canonical IÃ_ºB kinase (IKK) complex, which comprises the protein kinases IKKÃ_± and IKKÃ_Â_ and a regulatory subunit called NEMO. Protein ubiquitylation and protein phosphorylation events are known to be needed for the IKK complex to be activated: Met1-linked (or linear) polyubiquitin chains have to bind to NEMO, and the activation loops of IKKÃ_± and IKKÃ_Â_ have to become phosphorylated by the protein kinase TAK1. Intriguingly, the activation of TAK1 itself requires the binding of Lys63-linked ubiquitin chains to its regulatory subunits TAB2 and TAB3.
There has been an intense debate about the relative roles and importance of Lys63-linked versus Met1-linked ubiquitin chains in the activation of the canonical IKK complex by inflammatory stimuli. Now Christoph Emmerich has introduced a new twist to this story by discovering that the TAK1-dependent activation of the IKK complex requires a new type of ubiquitin chain in which Met1-linked and Lys63-linked ubiquitin oligomers are attached covalently to one another as 'hybrid' ubiquitin chains. In the same paper Sam Strickson found that the formation of Lys63-linked ubiquitin chains is a pre-requisite for the formation of Met1-linked ubiquitin chains, since Met1-linked ubiquitin chains were not formed in response to interleukin-1 in cells lacking Ubc13, the E2 conjugating enzyme that specifies the formation of Lys63-linked ubiquitin chains. The authors point out that forming Lys63/Met1-linked hybrids makes more physiological sense than producing two different ubiquitin chains, because it enables the co-localisation of the canonical IKK complex and the TAK1 complex to the same polyubiquitin chain, which may facilitate the activation of the canonical IKK complex by TAK1.
The new paper also establishes that LUBAC (the Linear UBiquitin Assembly Complex) is the only E3 ligase that forms Met1-linked ubiquitin chains in response to IL-1, that HOIP is the catalytic subunit of LUBAC and that Met1-linked ubiquitin chains are required to increase the efficiency with which the canonical IKK complex is activated.
Although the paper will help to resolve the debate about the relative roles of Lys63-linked and Met1-linked ubiquitin chains in the activation of NFÃ_ºB, it also raises many interesting new questions. For example, are the Lys63/Met1-linked ubiquitin hybrids formed in response to IL-1 also produced during the activation of other cellular processes? What is the precise topology of the ubiquitin oligomers in the hybrid molecules and what length do they need to be to activate NEMO-dependent processes efficiently? Do these ubiquitin chains need to be attached covalently to other proteins to control cellular events or are ubiquitin chains that are not anchored to any other protein sufficient for activation? What other proteins does NEMO interact with in an ubiquitin-dependent manner and what are their functions? What other protein kinases besides TAK1 are needed for the activation of the canonical IKK complex by signals other than IL-1? The answers to these and other questions will undoubtedly emerge from research performed in the years to come.