Helicobacter pylori -induced reactive oxygen species direct turnover of CSN-associated STAMBPL1 and augment apoptotic cell death
CELLULAR AND MOLECULAR LIFE SCIENCES(2022)
Abstract
Deubiquitinylases (DUBs) are central regulators of the ubiquitin system involved in protein regulation and cell signalling and are important for a variety of physiological processes. Most DUBs are cysteine proteases, and few other proteases are metalloproteases of the JAB1/MPN +/MOV34 protease family (JAMM). STAM-binding protein like 1 (STAMBPL1), a member of the JAMM family, cleaves ubiquitin bonds and has a function in regulating cell survival, Tax-mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and epithelial-mesenchymal transition. However, the molecular mechanism by which STAMBPL1 influences cell survival is not well defined, especially with regard to its deubiquitinylation function. Here, we show that reactive oxygen species (ROS) induced by chemotherapeutic agents or the human microbial pathogen Helicobacter pylori can induce cullin 1-RING ubiquitin ligase (CRL1) and 26S proteasome-dependent degradation STAMBPL1. Interestingly, STAMBPL1 has a direct interaction with the constitutive photomorphogenic 9 (COP9 or CSN) signalosome subunits CSN5 and CSN6. The interaction with the CSN is required for the stabilisation and function of the STAMBPL1 protein. In addition, STAMBPL1 deubiquitinylates the anti-apoptotic protein Survivin and thus ameliorates cell survival. In summary, our data reveal a previously unknown mechanism by which the deubiquitinylase STAMBPL1 and the E3 ligase CRL1 balance the level of Survivin degradation and thereby determine apoptotic cell death. In response to genotoxic stress, the degradation of STAMBPL1 augments apoptotic cell death. This new mechanism may be useful to develop therapeutic strategies targeting STAMBPL1 in tumours that have high STAMBPL1 and Survivin protein levels.
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Key words
Cullin-RING-ubiquitin ligase,Genotoxic stress,Ubiquitinylation
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