Phosphorylation of RelA/p65 on Serine 536 Defines an IκBα-independent NF-κB Pathway*

By C. Sasaki, T. Barberi, P. Ghosh, D. Longo. Journal of Biological Chemistry, 2005

310 citations recorded by the source corpus.

The association of the NF-κB p65/p50 dimer with IκBα plays a pivotal role in regulating its nuclear translocation and gene transcription. In addition, serine phosphorylation at various sites of the p65 subunit has been shown to be important in initiating transcription. Here we demonstrate that the regulation of nuclear translocation of p65 phosphorylated at serine 536 is not dependent on IκBα. Stimulation of either Jurkat or normal human T cells resulted in the nuclear translocation of phospho-p65 (Ser536). In addition, the phospho-p65 (Ser536) was not associated with either IκBα or p50, and the nuclear translocation of phospho-p65 (Ser536), but not total p65, was unaffected by the proteosome inhibitor MG-132, which blocks IκB protein degradation and prevents p65/p50 dimer nuclear translocation. Accordingly, the co-expression of a dominant negative mutant of IκBα blocked the transcriptional activity mediated by wild type but not the dominant positive p65 mutant (S536D). Furthermore, the transfection of the S536D form of p65 led to the induction of interleukin-8 transcription following stimulation, whereas the S536A form, which cannot be phosphorylated at this site, did not. Together, the findings suggest that p65 phosphorylated on serine 536 is not associated with or regulated by IκBα, that it has a distinct set of target genes, and that it may represent a noncanonical NF-κB pathway that is independent of IκBα regulation.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/ef55e8f55ad6194d877e5efaca7697801e4cb872

How researchers see this paper

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In Cancer Research

1. N. Perkins
2. T. Gilmore
3. S. Ghosh

In Immunology

1. N. Perkins
2. T. Gilmore
3. S. Ghosh

Citations in the corpus

• Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway (2006, background): “However, phosphorylation of Ser-536 can also result in an IkB-independent mechanism of NF-kB activation (Bohuslav et al., 2004; Sasaki et al., 2005).”
• Good cop, bad cop: the different faces of NF-κB (2006, background): “In addition, various stimuli in T cells can promote nuclear translocation of Ser-536-phosphorylated RelA, independent of IkBa or the proteasome.(29) In macrophages, IKKa has also been shown to phosphorylate RelA at Ser-536; however, in this case, Ser-536 phosphorylation results in proteolytic degrad”
• The Regulation of NF-κB Subunits by Phosphorylation (2016, result): “These studies support previous reports that p65 phosphorylated at S536 is not associated with, or regulated by, IκBα and that S536 phosphorylation may lead to the expression of a distinct set of target genes [94].”