| FBA8 | |
| Project ID |  FBA8 [Protein] |
| Project Theme | Mechanism underlying selective activation of NF-kB via linear polyubiquitination |
| Project Theme (short) | Ubiquitin activation of NF-kB |
| Principal Investigator | Kazuhiro Iwai |
| Affiliation | Graduate School of Frontier Biosciences, Osaka University |
| Backgrounds | - We discovered a new type of the linear polyubiquitin chain generated by a unique ubiquitin ligase complex LUBAC - LUBAC-mediated linear ubiquitination leads to the activation of NF-κB which has been implicated in cancer, inflammatory and autoimmune diseases |
| Highlights | - We identified SHARPIN as the third component of ubiquitin ligase complex LUBAC in addition to the previously reported HOIL-1L (RBCK1) and HOIP (RNF31) - Deletion of SHARPIN drastically reduced the amount of LUBAC and resulted in attenuated activation of NF-κB, leading to chronic dermatitis and an immunodeficiency - Chemical screening was started to find compounds that inhibit the activity of LUBAC |
| Outline | The ubiquitin-conjugation system regulates a vast range of biological phenomena by affecting protein function mostly through polyubiquitin conjugation. Polyubiquitin chains were thought to be formed only by the conjugation of the ubiquitin carboxy-terminal glycine to an internal lysine residue of another ubiquitin. However, we have identified a new type of the linear polyubiquitin chain in which the C-terminal glycine of ubiquitin is conjugated to the α-amino group of the amino-terminal methionine of another ubiquitin. Linear polyubiquitin is generated by a unique ubiquitin ligase complex LUBAC. LUBAC is composed of two huge proteins, HOIL-1L and HOIP. LUBAC-mediated linear ubiquitination of NEMO is involved specifically in NF-κB activation. NF-κB is a dimeric transcription factor and has been linked to cancer, inflammatory and autoimmune diseases. Here, we determine the structures and functions of various domains in HOIL-1L and HOIP proteins to reveal the molecular mechanism of LUBAC-mediated NF-κB activation. |
| Review | EMBO Rep. |
| CSML File | FBA8.csml |