Biophysical and biological evaluation of optimized stapled peptide inhibitors of the linear ubiquitin chain assembly complex (LUBAC).
Biophysical and biological evaluation of optimized stapled peptide inhibitors of the linear ubiquitin chain assembly complex (LUBAC).
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DOI：
10.1016/j.bmc.2017.11.047
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发表时间：
2018-03-15
影响因子：
3.5
通讯作者：
Bernal F
中科院分区：
文献类型：
--
作者：
Aguilar-Alonso F;Whiting AL;Kim YJ;Bernal F
线性泛素化是一种独特的细胞信号机制，泛素单位通过N-端和C-端氨基酸共价连接。这一过程是由一个单一的E3泛素连接酶--线性泛素链组装复合体(LUBAC)控制的，该复合体由HOIL-1L、HOIP和Sharpin三种蛋白质组成。LUBAC参与了典型的NF-κB途径的激活，并与依赖于NF-κB的恶性肿瘤有关。在这项工作中，我们提出了基于HOIP的装订的α-螺旋肽，旨在通过破坏HOIL-1L-HOIP相互作用和失去功能复合体来抑制LUBAC。我们发现我们的HOIP多肽在体外是活性的LUBAC泛素化抑制剂，尽管是通过与HOIP而不是HOIL相互作用。活性多肽对细胞活力有抑制作用，降低了核因子-κB活性，减少了核因子-κB相关基因产物的产生。这项工作进一步证明了LUBAC作为治疗靶点的潜力，以及使用装订的多肽作为蛋白质-蛋白质相互作用的抑制剂。
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.
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影响因子：
7
作者：
Wittig, Ilka;Karas, Michael;Schaegger, Hermann
通讯作者：
Schaegger, Hermann
影响因子：
3.7
作者：
Chen, Zhi-Dong;Xu, Liang;Mo, Shi-Jing
通讯作者：
Mo, Shi-Jing
影响因子：
8.7
作者：
Shimizu Y;Taraborrelli L;Walczak H
通讯作者：
Walczak H
影响因子：
64.8
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
通讯作者：
Dikic, Ivan
影响因子：
50.3
作者：
Bernal F;Wade M;Godes M;Davis TN;Whitehead DG;Kung AL;Wahl GM;Walensky LD
通讯作者：
Walensky LD