THE COP9 SIGNALOSOME COMPLEX RESPONSES TO OXIDATIVE STRESS

Reactive oxygen species (ROS) are now recognized as ubiquitous components of signal transduction pathways involved in various physiological processes. ROS mediated signalling (a.k.a. redox signalling) largely occurs through reversible oxidation of critical thiol groups on proteins. Crosstalk between thiol redox modifications and other post-translational modifications (PTMs) has recently emerged as an important intra cellular signalling mechanism.

A fundamental cellular mechanism driven by thiol-based enzymes is the PTM of proteins by ubiquitin (Ub) and ubiquitin-like (UBL) modifiers (such as SUMO, NEDD8/Rub1, ISG15, etc.). The modification of proteins by Ub/UBLs involves cognate cascades of enzymes; many of them include catalytic cysteine thiol groups. We recently showed that the cellular redox state plays as a molecular ON/OFF switch of the NEDD8/Rub1 cascade of enzymes. Targets of NEDD8/Rub1 are primarily "cullins", a family of scaffold proteins on which modular cullin-RING ubiquitin E3 ligases (CRLs) are built. The attachment of NEDD8/Rub1 to cullins activate hundreds of CRLs and mediate ~20% of protein ubiquitination. Cullin NEDDylation is reversed by a multi-subunit enzyme, known as the COP9 signalosome (CSN).

We aim to examine the effect of oxidation on integrity and function of the CSN holocomplex and individual subunits. Our recent data shows that the CSN is sensitive to oxidative stress. We found that at least 3 of the subunits are targeted by ROS in a reversible manner, including the catalytic subunit, Csn5/Jab1. We are currently trying to understand if and how these modifications alter various regulatory roles of the CSN, as well as complex integrity and turnover.