The Emerging Role of Deubiquitinases in Cell Death

Abstract

Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, including mono- or polyubiquitination. Functionally, ubiquitination can affect protein abundance, localization, and activity. Like other post-translational modifications, ubiquitination is a dynamic and reversible process mediated by deubiquitinases, a large class of proteases that cleave ubiquitin from proteins and other substrates. The balance between ubiquitination and deubiquitination machinery determines cell fate under stressful conditions. Here, we review the latest advances in our understanding of the role of deubiquitinases in regulating the main types of RCD, including apoptosis, necroptosis, pyroptosis, and ferroptosis. This knowledge may contribute to identifying new protein degradation-related prognostic markers and therapeutic targets for human disease.

USP15 promotes the progression of papillary thyroid cancer by regulating HMGB1 stability through its deubiquitination

“…Studies have shown that USP15 knockdown induced downregulation of estrogen receptor alpha protein by promoting its K48-related ubiquitination, which is necessary for proliferation inhibition of breast cancer cells 46 . Similarly, when USP15 was overexpressed, the HGMB1 protein level decreased due to the reduction of its associated ubiquitination by transfecting the K48R mutant into PTC cells 47 . Moreover, the development of malignant tumors, including invasion and metastasis, depended on the integrity of the basement membrane and extracellular matrix.…”