New research has uncovered how a complex protein pivotal in the development of viral infection and autoimmune diseases is activated. The discovery answers a key question about one of the most widely-researched proteins in human biology, which has been the subject of tens of thousands of research papers.
Jiazhen Zhang, a research student in Philip Cohen's laboratory, uncovered how the canonical IÃ_ºB kinase is activated. The results are published today in the Biochemical Journal.
NF-Ã_ºB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA. NF-Ã_ºB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-Ã_ºB has been linked to inflammatory, and autoimmune diseases, septic shock, viral infection.
'NF-Ã_ºB has been the subject of a vast amount of research for many years as it plays a critical role in inflammatory diseases and cancer,' said Sir Philip. 'It has been known for some time that the protein is activated by a kinase called IKKÃ_Â_ but there has been split opinion with regards to how the kinase itself is switched on.
'We have confirmed that another kinase, TAK1, is involved, but surprisingly it isn't sufficient to switch on IKKÃ_Â_. Two other events need to happen in addition, namely the formation of a hybrid ubiquitin chain and its attachment to the NEMO regulatory component of the canonical IKK complex as we showed in a paper last year (Emmerich (2013) PNAS, 110, 15247) and then the addition of a second phosphate group on to IKKÃ_Â_ which remarkably is carried out by IKKïÂÅ¢ itself. It is only then that IKKÃ_Â_ becomes competent to switch on NF-Ã_ºB.
'This is complex biochemistry but working out the details of how proteins are switched on and off is how new ways to develop improved drugs to treat disease are identified. For example, the enzyme that makes the ubiquitin chains needed to activate IKKÃ_Â_ could now be targeted to develop a drug to treat inflammatory diseases.'
Peter Shepherd, Chair of the Biochemical Journal Editorial Board, said, 'This signalling pathway is critical for a wide range of cellular responses, particularly stress responses. Understanding how this pathway is regulated is hugely important, and this paper finally clarifies one of the key steps in this process. This is important in not only understanding the disease process, but in the quest to develop new therapies that target this signalling pathway.'
Jiazhen Zhang, a research student in Philip Cohen's laboratory, uncovered how the canonical IÃ_ºB kinase is activated. The results are published today in the Biochemical Journal.
NF-Ã_ºB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA. NF-Ã_ºB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-Ã_ºB has been linked to inflammatory, and autoimmune diseases, septic shock, viral infection.
'NF-Ã_ºB has been the subject of a vast amount of research for many years as it plays a critical role in inflammatory diseases and cancer,' said Sir Philip. 'It has been known for some time that the protein is activated by a kinase called IKKÃ_Â_ but there has been split opinion with regards to how the kinase itself is switched on.
'We have confirmed that another kinase, TAK1, is involved, but surprisingly it isn't sufficient to switch on IKKÃ_Â_. Two other events need to happen in addition, namely the formation of a hybrid ubiquitin chain and its attachment to the NEMO regulatory component of the canonical IKK complex as we showed in a paper last year (Emmerich (2013) PNAS, 110, 15247) and then the addition of a second phosphate group on to IKKÃ_Â_ which remarkably is carried out by IKKïÂÅ¢ itself. It is only then that IKKÃ_Â_ becomes competent to switch on NF-Ã_ºB.
'This is complex biochemistry but working out the details of how proteins are switched on and off is how new ways to develop improved drugs to treat disease are identified. For example, the enzyme that makes the ubiquitin chains needed to activate IKKÃ_Â_ could now be targeted to develop a drug to treat inflammatory diseases.'
Peter Shepherd, Chair of the Biochemical Journal Editorial Board, said, 'This signalling pathway is critical for a wide range of cellular responses, particularly stress responses. Understanding how this pathway is regulated is hugely important, and this paper finally clarifies one of the key steps in this process. This is important in not only understanding the disease process, but in the quest to develop new therapies that target this signalling pathway.'