Transcription factor p65 (RelA) Lysine 310 acetylation (NF-κB p65 K310ac)

Transcription factor p65 (RelA) Lysine 310 (K310) acetylation is a critical post-translational modification that dictates the transcriptional potency and duration of the NF-κB-mediated inflammatory response. While the activation of NF-κB typically involves the degradation of IκB and subsequent nuclear translocation of the p65/p50 heterodimer, the acetylation of p65 at K310 by the acetyltransferases p300 and CBP is required for full transcriptional activity (Chen et al., 2002, PMID: 12169597). This modification enhances the DNA-binding affinity of p65 and is essential for the recruitment of the bromodomain-containing protein BRD4, which facilitates the assembly of the transcription elongation complex at target gene promoters (Huang et al., 2009, PMID: 19015315). Conversely, the deacetylation of K310 by sirtuins, particularly SIRT1, or histone deacetylases like HDAC3, serves as a key regulatory mechanism to terminate NF-κB-dependent gene expression (Yeung et al., 2004, PMID: 15175242). In pathological states such as chronic inflammation, autoimmune disorders, and various cancers, p65 K310 acetylation is often constitutively elevated, driving the persistent expression of pro-inflammatory cytokines and anti-apoptotic factors. Consequently, this modification has emerged as a significant therapeutic target. Pharmacological strategies include the use of SIRT1 activators (e.g., Resveratrol, SRT1720) to promote deacetylation or p300/CBP inhibitors (e.g., C646, A-485) to prevent the modification, thereby dampening hyper-inflammatory signaling (Ghizzoni et al., 2011, PMID: 21254713; Lasko et al., 2017, PMID: 28953875). Additionally, BET inhibitors like JQ1 target the reader of this modification, BRD4, providing an alternative method to disrupt NF-κB-driven disease progression. However, therapeutic development must balance the need for potent inhibition with the risk of systemic immunosuppression and off-target effects associated with modulating broad-acting enzymes.

Other names

p65 K310 acetylationRelA Lys310 acetylationAcetylated-RelA (Lys310)NF-kappaB p65-K310acNF-κB p65 – Lys310 acetylation–dependent activity

Modulation of NF-κB transcriptional activity by regulating the acetylation status of the p65 (RelA) subunit at the Lysine 310 residue. Acetylation by p300/CBP promotes DNA binding and recruitment of the co-activator BRD4, while deacetylation by SIRT1 or HDAC3 terminates the transcriptional response.