CD40 stimulates a "feed-forward" NF-?B-driven molecular pathway that regulates IFN-? expression in carcinoma cells.

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CD40 stimulates a "feed-forward" NF-?B-driven molecular pathway that regulates IFN-? expression in carcinoma cells.

J Immunol. 2012 Jun 1;188(11):5521-7

Authors: Moschonas A, Ioannou M, Eliopoulos AG

Abstract
IFN-? and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-? upregulation through an unconventional "feed-forward" mechanism, which is orchestrated by canonical NF-?B and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-?B, IRF1, and Viperin-dependent IRF7 binding to the IFN-? promoter largely controls its activity. However, full activation of IFN-? also requires the parallel engagement of noncanonical NF-?B2 signaling leading to p52 recruitment to the IFN-? promoter. These data define a novel link between CD40 signaling and IFN-? expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression.

PMID: 22547704 [PubMed - indexed for MEDLINE]

NF-kB pathway NF-kB signaling NF-kappaB signaling pathway

Cooperative roles of NF-?B and NFAT4 in polyomavirus JC regulation at the KB control element.

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Cooperative roles of NF-?B and NFAT4 in polyomavirus JC regulation at the KB control element.

Virology. 2012 Oct 10;432(1):146-54

Authors: Wollebo HS, Melis S, Khalili K, Safak M, White MK

Abstract
The human polyomavirus JC (JCV) is the causative agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML). Infection by JCV is extremely common and after primary infection, JCV persists in a latent state. However, PML is a very rare disease suggesting that the virus is tightly regulated. Previously, we showed that NF-?B and C/EBP? regulate the JCV early and late promoters via a DNA control element, KB, which also mediates the stimulatory effects of proinflammatory cytokines such as TNF-? on JCV gene expression. Other studies have implicated NFAT4 in JCV regulation. We now report that NFAT4 and NF-?B interact at the KB element to co-operatively activate both JCV early and late transcription and viral DNA replication. This interplay is inhibited by C/EBP? and by agents that block the calcineurin/NFAT signaling pathway. The importance of these events in the regulation of JCV latency and reactivation is discussed.

PMID: 22749879 [PubMed - in process]

NF-kB signaling pathway NF-kB pathway NF-kB signaling

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