This results in the activation of IkB kinase complex consisting of the catalytic IKKa and b subunits and the regulatory subunit IKK-c/NEMO. IKK activation involves conjugation of Lys63-linked polyubiquitin chains to NEMO and its upstream regulators like RIP. RIP has emerged as a central adaptor in the pathways leading to IKK and NF-kB activation and also cell death. Following TNFa stimulation RIP is recruited to TNFR1 signalling complex and is rapidly ubiquitinated with Lys63-linked polyubiquitin chains. NEMO binds to polyubiquitinated RIP through its ubiquitin binding domain resulting in the activation of catalytic subunits of IKK. The recognition and association of ubiquitinated RIP with NEMO is essential for IKK activation. The activated catalytic subunits of IKK then phosphorylate IkB triggering its ubiquitination and degradation leading to nuclear translocation and activation of NF-kB. Given its role in diverse cellular processes, the activation of NF-kB is governed by several positive and negative regulators. With the increasing roleof ubiquitination, deubiquitinases like CYLD and A20 have emerged as key negative regulators of NF-kB activation. CYLD was originally identified as a tumor suppressor gene mutated in familial cylindromas. It is the first deubiquitinase shown to inhibit IKK activation. CYLD specifically catalyses cleavage of Lys63-linked polyubiquitin chains from its target proteins like RIP, NEMO and TRAFs to prevent NF-kB activation. Though CYLD targets multiple NF-kB signalling molecules, the mechanism by which CYLD recognises its substrate RIP to regulate NF-kB activation is not completely understood. Optineurin was recently identified as a negative regulator of NF-kB signalling whose expression is governed by NF-kB. It is a multifunctional protein involved in membrane trafficking, signal transduction, anti-viral responses and gene expression. The C-terminal region of optineurin has a novel bipartite UBD which shows homology with NEMO and ABIN1. This UBD of Optineurin, like NEMO, preferentially binds to Lys63-linked ubiquitin chains and does not show significant binding to Lys48-linked polyubiquitin chains. It was suggested that optineurin binds to polyubiquitinated RIP through its UBD to prevent association of NEMO with RIP, thus inhibiting NF-kB activation. Optineurin was identified as a gene mutated in certain glaucomas, a group of neurodegenerative eye diseases that cause blindness, and recently in familial amyotrophic lateral sclerosis. However, the nature of functional defects caused by mutations in optineurin is beginning to be BKM120 abmole bioscience understood only now. Recently we have identified CYLD as an interacting protein of optineurin in a yeast-two hybrid screen. This was reported briefly in a review without showing any data. However the functional significance of this interaction is not known. Since optineurin interacts with CYLD, the role of optineurin in the regulation of NF-kB signalling is likely to be complex.