NF-κB Repression by PIAS3 Mediated RelA SUMOylation

Abstract

Negative regulation of the NF-κB transcription factor is essential for tissue homeostasis in response to stress and inflammation. NF-κB activity is regulated by a variety of biochemical mechanisms including phosphorylation, acetylation, and ubiquitination. In this study, we provide the first experimental evidence that NF-κB is regulated by SUMOylation, where the RelA subunit of NF-κB is SUMOylated by PIAS3, a member of the PIAS (protein inhibitor of activated STAT) protein family with E3 SUMO ligase activity. PIAS3-mediated NF-κB repression was compromised by either RelA mutant resistant to SUMOylation or PIAS3 mutant defective in SUMOylation. PIAS3-mediated SUMOylation of endogenous RelA was induced by NF-κB activation thus forming a negative regulatory loop. The SUMOylation of endogenous RelA was enhanced in IκBα null as compared with wild type fibroblasts. The RelA SUMOylation was induced by TNFα but not leptomycin B mediated RelA nuclear translocation. Furthermore, RelA mutants defective in DNA binding were not SUMOylated by PIAS3, suggesting that RelA DNA binding is a signal for PIAS3-mediated SUMOylation. These results support a novel negative feedback mechanism for NF-κB regulation by PIAS3-mediated RelA SUMOylation.

HIV-1 gp120 Activates the STAT3/Interleukin-6 Axis in Primary Human Monocyte-Derived Dendritic Cells

“…Importantly, the IL-6 transcript accumulation and protein secretion in response to gp120 also is reversed in the presence of various STAT3 inhibitors, providing support for a role of early STAT3 activation in the production of IL-6 in our cell model. We also show that STAT3 activation parallels a concomitant upmodulation of PIAS3, a factor playing a major role in the inhibition of STAT3 and NF-B activation (39,52,53). Persistent STAT3 activation despite PIAS3 accumulation further suggests that the JAK/STAT pathway is dysregulated upon MDDC exposure to gp120.…”

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

“…Thus, PIAS can interact with diverse proteins and regulate multiple signaling cascades, which modulate varied cellular functions, such as survival, proliferation, and migration (13)(14)(15). Therefore, PIAS proteins act as regulators of transcription, either positively or negatively (12).…”

“…PIAS proteins contain four conserved structural domains and motifs: a SAP region for chromatin binding, RING (an interesting new gene) finger-like zinc-binding domain for E3-SUMO ligation, a SUMO-interacting motif for SUMO binding, and PINIT motif for localization (12). In addition to cell proliferation, apoptosis, and signal transduction (13)(14)(15), PIAS proteins also regulate cell migration and invasion of some cell lines. For example, PIASy enhances epithelial cell migration through alteration of C/EBPd nuclear localization and reduction of C/EBPd transcriptional activity (16).…”

Electrophilic Lipid Mediator 15-Deoxy-Δ12,14-Prostaglandin J2 Modifies Glucocorticoid Signaling via Receptor SUMOylation

“…Interestingly, the NF-B and the AP1 are also subject to regulation by SUMOylation (49)(50)(51)(52). Both of them have been shown to mediate transcriptional responses to oxidative stress and inhibit the GR function (7,(53)(54)(55)(56).…”