期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：33
DOI：10.1073/pnas.2123097119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
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.
