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… Click to show full abstract
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.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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