Regulation of NF-κB Signaling by Pin1-Dependent Prolyl Isomerization and Ubiquitin-Mediated Proteolysis of p65/RelA

Abstract

The transcription factor NF-kappaB is activated by the degradation of its inhibitor IkappaBalpha, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…Ryo et al (2003) showed that Pin1 expression in human breast cancer samples correlates with nuclear levels of RelA. This study suggests that Pin1 binds to RelA, inhibiting interaction with IkB and resulting in increased nuclear accumulation of this NF-kB subunit (Figure 2).…”

Current insights into the regulation of programmed cell death by NF-κB

“…It remains to be determined whether differences in experimental conditions account for these different observations. In contrast to factors that antagonize NF-kB's transcriptional and protective activities, the peptidyl prolyl-isomerase Pin1 enhances nuclear accumulation of RelA by blocking its association with IkBa and by interfering with suppressor of cytokine signalling 1 (SOCS-1)-dependent ubiquitination and degradation of RelA (Ryo et al, 2003). Although direct evidence is still lacking about whether Pin1 enhances the protective activity of NF-kB, Pin1 is frequently upregulated in breast cancer and in mouse mammary tumors (Ryo et al, 2003;Currier et al, 2005).…”

“…In contrast to factors that antagonize NF-kB's transcriptional and protective activities, the peptidyl prolyl-isomerase Pin1 enhances nuclear accumulation of RelA by blocking its association with IkBa and by interfering with suppressor of cytokine signalling 1 (SOCS-1)-dependent ubiquitination and degradation of RelA (Ryo et al, 2003). Although direct evidence is still lacking about whether Pin1 enhances the protective activity of NF-kB, Pin1 is frequently upregulated in breast cancer and in mouse mammary tumors (Ryo et al, 2003;Currier et al, 2005). A recently published report indicates that the intracellular domain of Notch (Notch-IC) interacts with NF-kB to compete with IkBa, consequently enhancing NF-kB's nuclear retention and sustained NF-kB activity (Shin et al, 2006).…”

Pin1 overexpression is associated with poor differentiation and survival in oral squamous cell carcinoma

“…Moreover, the interaction of Pin1 and phosphorylated p65/RelA subunit of NFκB prevents NFκB from binding to IκB that increases its transcriptional activity and consequentially elevate the cyclin D1 level (36). Besides upregulation of the cyclin D1 gene expression, Pin1 has been demonstrated to directly bind to pT286-Pro motif of cyclin D1 and resulted in increasing its protein stability (37).…”