Immune Differentiation Regulator p100 Tunes NF-κB Responses to TNF

Abstract

Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation

“…Despite being apparently functionally normal in young mice, the Nfkb2 −/− Tregs in our study do show some altered characteristics reported previously as well, namely, reduced levels of CTLA-4 and enhanced GITR levels possibly related to heightened noncanonical NF-κB signaling 48,71 . It has been shown earlier that an absence of Nfkb2-p100 provokes enhanced RelB:p50 activity via the canonical NF-κB pathway in mouse embryonic fibroblasts, and that RelB:p50 induces a distinct set of genes, which are not activated by RelA:p50 and are associated with cell survival and cell division 72 . Our biochemical analyses revealed heightened nuclear activity of RelB:p50 in functionally normal Nfkb2 −/− Tregs, while our global transcriptomic studies established an altered gene expression pattern in them favoring pro-survival and pro-proliferative functions.…”

Construction and validation of an aging‐related gene signature for prognosis prediction of patients with breast cancer

“…NFKB2 has frequent mutations in cancers, and it is related with abnormal TNF signal transduction and tumor diseases. 20 Moreover, NFKB2 is a target of MYC suppression. NFKB2 deficiency can accelerate the development of lymphoma in Eμ‐myc transgenic mice.…”

“…These events are triggered by many incentives related with many biological processes including inflammation, immunity, cell differentiation, cell cycle, tumor initiation, and cell apoptosis. NFKB2 has frequent mutations in cancers, and it is related with abnormal TNF signal transduction and tumor diseases 20 . Moreover, NFKB2 is a target of MYC suppression.…”

The NF-κB multidimer system model: A knowledge base to explore diverse biological contexts

“…Various lymphomas and leukemias, such as B cell chronic lymphocytic leukemia, multiple myeloma, and adult T-cell leukemia/lymphoma, have mutations in the nfkb2 gene, which encodes the protein p100 (56)(57)(58). Total loss of p100 in both knockout cell lines and multiple myeloma cells prolongs the NF-κB response to stimuli, providing a pro-survival response (30,59).…”