Forkhead box O (FOXO) transcription factors are involved in various cellular 
processes, including cell proliferation, stress resistance, metabolism, and 
longevity. Regulation of FOXO transcriptional activity occurs mainly through a 
variety of post-translational modifications, including phosphorylation, 
acetylation, and ubiquitination. Here we describe nemo-like kinase (NLK) as a 
novel regulator of FOXOs. NLK binds to and phosphorylates FOXO1, FOXO3a, and 
FOXO4 on multiple residues. NLK acts as a negative regulator of FOXO 
transcriptional activity. For FOXO4 we show that NLK-mediated loss of FOXO4 
activity co-occurs with inhibition of FOXO4 monoubiquitination. Previously, we 
have shown that oxidative stress-induced monoubiquitination of FOXO4 stimulates 
its transactivation, which leads to activation of an antioxidant defensive 
program. Conversely, NLK-dependent inhibition of FOXO4 activity can provide a 
means to downregulate this defensive program, when oxidative stress reaches a 
level beyond which repair is no longer feasible and cells need to undergo 
apoptosis.