EBV LMP1: New and shared pathways to NF-κB activation.

T he canonical NF-κB pathway plays a pivotal role in regulating a variety of essential processes, such as immunity, cell survival, and proliferation, and therefore must be tightly regulated to ensure a transient response to infection or other stimuli. When dysregulated, persistent NF-κB activation may fuel chronic inflammation and tumorigenesis in certain settings. NF-κB– activating stimuli converge at the level of the IκB kinase (IKK) complex consisting of catalytic subunits IKKα and IKKβ and a regulatory subunit IKKγ (also known as NEMO). IKK phosphorylates the NF-κB inhibitor IκBα to trigger its ubiquitination and proteasomal degradation, thus allowing NF-κB subunits to translocate to the nucleus and activate target genes (1, 2). A large number of both positive and negative regulators of NF-κB have been identified, although there are likely many more to be found. An effective and powerful approach to finding new mediators of NF-κB activation is used by Gewurz et al. (3) in a study published in PNAS, whereby the authors conduct genome-wide screening using an siRNA library to identify novel regulators of EBV-encoded latent membrane protein 1 (LMP1)-induced activation of NF-κB.