Reciprocal interplay between OTULIN-LUBAC determines genotoxic and inflammatory NF-κB signal responses.
Reciprocal interplay between OTULIN-LUBAC determines genotoxic and inflammatory NF-κB signal responses.
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DOI：
10.1073/pnas.2123097119
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发表时间：
2022-08-16
影响因子：
11.1
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中科院分区：
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去遍在蛋白酶已成为一类新的调节核因子-κ B（NF-κB）信号传导的调节剂。卵巢肿瘤家族去泛素化酶OTULIN通过抵消线性泛素链组装复合物（LUBAC）抑制NF-κB活化。临床上，OTULIN功能丧失导致OTULIN相关的自身炎症综合征。在这里，我们证明了OTULIN功能丧失导致实验性癌症模型中的化学抗性。此外，我们发现在正常和遗传毒性/炎症条件下的分子事件，涉及LUBAC依赖性线性泛素化和氧化应激介导的通过二硫键的OTULIN二聚化。这些事件在化疗耐药乳腺组织的临床标本中得到了有力支持。鉴于NF-κ B介导的过度炎症在当前流行病中的核心作用，专注于稳定OTULIN-LUBAC相互作用的策略可能为未来的药物开发提供选择。靶向核因子-κ B（NF-κB）代表了一种针对癌症化疗耐药性以及细胞死亡的高度可行的策略。泛素化（包括由线性泛素链组装复合物（LUBAC）介导的线性泛素化）是NF-κB信号过度激活的重要机制。卵巢肿瘤家族去泛素化酶OTULIN是唯一的线性连接特异性去泛素化酶;然而，它如何抵消LUBAC介导的NF-κB激活的分子机制在很大程度上是未知的。在此，我们鉴定了以LUBAC依赖性方式促进的OTULIN的Lys 64/66的线性泛素化作为在非应激条件下OTULIN-LUBAC相互作用所需的必要事件，其响应于遗传毒性应激而被OTULIN本身去泛素化。此外，这种由OTULIN二聚化介导的OTULIN自身去泛素化发生在分子间，导致随后OTULIN从LUBAC复合物中解离和NF-κB过度活化。氧化应激通过半胱氨酸介导的共价二硫键诱导OTULIN二聚化。我们的研究表明，通过细胞存活和增殖测量，OTULIN和LUBAC之间的物理相互作用状态是基因毒性NF-κB信号传导的关键决定因素，而由其二聚化和去泛素化导致的OTULIN功能丧失导致OTULIN从LUBAC复合物中解离。值得注意的是，类似的分子机制适用于响应肿瘤坏死因子α的炎症NF-κB信号传导。因此，更全面地了解破坏OTULIN-LUBAC相互作用的详细分子机制将有助于开发针对与许多人类疾病相关的癌症化学抗性和坏死性凋亡过程的未来治疗策略。
Deubiquitinases have emerged as a new class of modulators governing nuclear factor-kappa B (NF-κB) signaling. Ovarian tumor family deubiquitinase OTULIN inhibits NF-κB activation via counteracting the linear ubiquitin chain assembly complex (LUBAC). Clinically, OTULIN loss of function leads to OTULIN-related autoinflammatory syndrome. Here, we demonstrate that OTULIN loss of function leads to chemoresistance in experimental cancer models. Moreover, we discover molecular events under normal and genotoxic/inflammatory conditions involving LUBAC-dependent linear ubiquitination and oxidative stress–mediated dimerization of OTULIN through disulfide bonds. These events are strongly supported in clinical specimens of chemoresistant breast tissue. Given the central role of NF-κB–mediated hyperinflammation upon current pandemic, strategies focusing on stabilizing the OTULIN–LUBAC interaction may provide options in future drug development. Targeting nuclear factor-kappa B (NF-κB) represents a highly viable strategy against chemoresistance in cancers as well as cell death. Ubiquitination, including linear ubiquitination mediated by the linear ubiquitin chain assembly complex (LUBAC), is emerging as a crucial mechanism of overactivated NF-κB signaling. Ovarian tumor family deubiquitinase OTULIN is the only linear linkage–specific deubiquitinase; however, the molecular mechanisms of how it counteracts LUBAC-mediated NF-κB activation have been largely unknown. Here, we identify Lys64/66 of OTULIN for linear ubiquitination facilitated in a LUBAC-dependent manner as a necessary event required for OTULIN–LUBAC interaction under unstressed conditions, which becomes deubiquitinated by OTULIN itself in response to genotoxic stress. Furthermore, this self-deubiquitination of OTULIN occurs intermolecularly, mediated by OTULIN dimerization, resulting in the subsequent dissociation of OTULIN from the LUBAC complex and NF-κB overactivation. Oxidative stress induces OTULIN dimerization via cysteine-mediated covalent disulfide bonds. Our study reveals that the status of the physical interaction between OTULIN and LUBAC is a crucial determining factor for the genotoxic NF-κB signaling, as measured by cell survival and proliferation, while OTULIN loss of function resulting from its dimerization and deubiquitination leads to a dissociation of OTULIN from the LUBAC complex. Of note, similar molecular mechanisms apply to the inflammatory NF-κB signaling in response to tumor necrosis factor α. Hence, a fuller understanding of the detailed molecular mechanisms underlying the disruption of the OTULIN–LUBAC interaction will be instrumental for developing future therapeutic strategies against cancer chemoresistance and necroptotic processes pertinent to numerous human diseases.
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影响因子：
39.3
作者：
Liu T;Zhang L;Joo D;Sun SC
通讯作者：
Sun SC
DOI：
10.1073/pnas.0403621101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Biswas, DK;Shi, Q;Iglehart, JD
通讯作者：
Iglehart, JD
影响因子：
8.1
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Hojyo S;Uchida M;Tanaka K;Hasebe R;Tanaka Y;Murakami M;Hirano T
通讯作者：
Hirano T
影响因子：
15.9
作者：
Baldwin, AS
通讯作者：
Baldwin, AS
影响因子：
30.5
作者：
通讯作者：
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