The NF-κB Activation in Lymphotoxin β Receptor Signaling Depends on the Phosphorylation of p65 at Serine 536

Abstract

NF-B-inducing kinase (NIK) has been shown to play an essential role in the NF-B activation cascade elicited by lymphotoxin ␤ receptor (LT␤R) signaling. However, the molecular mechanism of this pathway remains unclear. In this report we demonstrate that both NIK and IB kinase ␣ (IKK␣) are involved in LT␤R signaling and that the phosphorylation of the p65 subunit at serine 536 in its transactivation domain 1 (TA1) plays an essential role. We also found that NF-B could be activated in the LT␤R pathway without altering the level of the phosphorylation of IB and nuclear localization of p65. By using a heterologous transactivation system in which Gal4-dependent reporter gene is activated by the Gal4 DNA-binding domain in fusion with various portions of p65, we found that TA1 serves as a direct target in the NIK-IKK␣ pathway. In addition, mutation studies have revealed the essential role of Ser-536 within TA1 of p65 in transcriptional control mediated by NIK-IKK␣. Furthermore, we found that Ser-536 was phosphorylated following the stimulation of LT␤R, and this phosphorylation was inhibited by the kinase-dead dominant-negative mutant of either NIK or IKK␣. These observations provide evidence for a crucial role of the NIK-IKK␣ cascade for NF-B activation in LT␤R signaling.

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

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Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia

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Human T-cell Lymphotropic Virus Type 1 Tax Induction of Biologically Active NF-κB Requires IκB Kinase-1-mediated Phosphorylation of RelA/p65

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