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Nat Cell Biol. 2009 Feb;11(2):123-32. doi: 10.1038/ncb1821. Epub 2009 Jan 11.
Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation.
Tokunaga F1, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, Nakagawa T, Kato M, Murata S, Yamaoka S, Yamamoto M, Akira S, Takao T, Tanaka K, Iwai K.
(Suomennosta) Tumatekijä NF-kB on avainasemassa oleva transkriptiotekijä tulehduksellisissa, anti-apoptoottisissa ja immuuniprosesseissa. Ubikitiinitie on kriittisen tärkeä NF-kB-tien säätelyssä. Tässä tutkijat ovat löytäneet LUBAC-ligaasikompleksin, jossa on kaksi RING finger proteiinia HOIL-1L ja HOIP ja se konjugoivat lineaarisia polyubikitiiniketjuja substraatteihin.
Tässä tutkijat osoittavat, että LUBAC aktivoi kanonisen NF-kB tien sitoutumalla NEMOon ja konjugoimalla polyubikitiiniketjuja NEMOn spesifisiin lysiineihin NEMOn CC2-LZ- domaaniin (Ubc12:sta riippumattomalla tavalla) . .. Poistogeenisin tutkimuksin osoitettiin, että LUBAC osallistuu kanonisen NFkB aktivaatiotien fysiologiseen säätelyyn tekemällä NEMO:n lineaarisia polyubikitinaatioita
Abstract Nuclear factor-kappaB (NF-kappaB) is a key transcription factor in inflammatory, anti-apoptotic and immune processes. The ubiquitin pathway is crucial in regulating the NF-kappaB pathway. We have found that the LUBAC ligase complex, composed of the two RING finger proteins HOIL-1L and HOIP, conjugates a head-to-tail-linked linear polyubiquitin chain to substrates. Here, we demonstrate that LUBAC activates the canonical NF-kappaB pathway by binding to NEMO (NF-kappaB essential modulator, also called IKKgamma) and conjugates linear polyubiquitin chains onto specific Lys residues in the CC2-LZ domain of NEMO in a Ubc13-independent manner.
Moreover, in HOIL-1 knockout mice and cells derived from these mice, NF-kappaB signalling induced by pro-inflammatory cytokines such as TNF-alpha and IL-1beta was suppressed, resulting in enhanced TNF-alpha-induced apoptosis in hepatocytes of HOIL-1 knockout mice.
These results indicate that LUBAC is involved in the physiological regulation of the canonical NF-kappaB activation pathway through linear polyubiquitylation of NEMO.Comment in Linear polyubiquitylation: the missing link in NF-kappaB signalling. [Nat Cell Biol. 2009]
Uusinta tästä LUBAC linear ubiquitin chain assembly complex) .- asiasta ( 11.4. 2018 linkki Saksasta parkinsontutkimuksesta
http://www.ruhr-uni-bochum.de/biochem/zellbio/research/ubiquitin.html.de
https://www.ruhr-uni-bochum.de/biochem/mam/images/fittosize_450_370_7000fc97ff2e4e315e8545af722117d6_figure3.jpeg
Bioorg Med Chem. 2018 Mar 15;26(6):1179-1188. doi: 10.1016/j.bmc.2017.11.047. Epub 2017 Dec 5.Biophysical and biological evaluation of optimized stapled peptide inhibitors of the linear ubiquitin chain assembly complex (LUBAC).Abstract
Linear ubiquitylation, in which ubiquitin units are covalently linked through N- and C-terminal amino acids, is a unique cellular signaling mechanism. This process is controlled by a single E3 ubiquitin ligase, the linear ubiquitin chain assembly complex (LUBAC), which is composed of three proteins - HOIL-1L, HOIP and SHARPIN. LUBAC is involved in the activation of the canonical NF-κB pathway and has been linked to NF-κB dependent malignancies. In this work, we present HOIP-based stapled alpha-helical peptides designed to inhibit LUBAC through the disruption of the HOIL-1L-HOIP interaction and loss of the functional complex. We find our HOIP peptides to be active LUBAC ubiquitylation inhibitors in vitro, though through interaction with HOIP rather than HOIL. Active peptides were shown to have inhibitory effects on cell viability, reduced NF-κB activity and decreased production of NF-κB related gene products. This work further demonstrates the potential of LUBAC as a therapeutic target and of the use of stapled peptides as inhibitors of protein-protein interactions.KEYWORDS:
Linear ubiquitylation; NF-κB; Protein-protein interactions; Stapled peptides
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