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HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-?B and depends on chronically activated IKK? and p65/RelA.

ABSTRACT: The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-?B pathways and is thought to promote cell proliferation and transformation via NF-?B activation. We showed recently that hyperactivation of NF-?B by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-?B activation by expression of I-?B? superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescence (Tax-IRS). Here we demonstrate that Tax-IRS is driven by the transcriptional activity of NF-?B. Knockdown of IKK?, the primary Tax target, by shRNAs abrogated Tax-mediated activation of both classical and alternative NF-?B pathways and rendered knockdown cells resistant to Tax-IRS. Consistent with a critical role of IKK? in the transcriptional activity of NF-?B, IKK? deficiency drastically decreased NF-?B trans-activation by Tax, although it only modestly reduced Tax-mediated I-?B? degradation and NF-?B nuclear localization. In contrast, although IKK? knockdown attenuated Tax-induced NF-?B transcriptional activation, the residual NF-?B activation in IKK?-deficient cells was sufficient to trigger Tax-IRS. Importantly, the phenotypes of NIK and TAK1 knockdown were similar to those of IKK? and IKK? knockdown, respectively. Finally, double knockdown of RelB and p100 had a minor effect on senescence induction by Tax. These data suggest that Tax, through its interaction with IKK?, helps recruit NIK and TAK1 for IKK? and IKK? activation, respectively. In the presence of Tax, the delineation between the classical and alternative NF-?B pathways becomes obscured. The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-?B, which depends on activated IKK? and p65/RelA.

SUBMITTER: Ho YK

PROVIDER: S-EPMC3416137 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-κB and depends on chronically activated IKKα and p65/RelA.

Ho Yik-Khuan YK Zhi Huijun H DeBiaso Dominic D Philip Subha S Shih Hsiu-Ming HM Giam Chou-Zen CZ

Journal of virology 20120627 17

The HTLV-1 oncoprotein Tax is a potent activator of classical and alternative NF-κB pathways and is thought to promote cell proliferation and transformation via NF-κB activation. We showed recently that hyperactivation of NF-κB by Tax triggers a cellular senescence response (H. Zhi et al., PLoS Pathog. 7:e1002025, 2011). Inhibition of NF-κB activation by expression of I-κBα superrepressor or by small hairpin RNA (shRNA)-mediated knockdown of p65/RelA rescues cells from Tax-induced rapid senescen ...[more]

PMID: 22740410

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Project description:The NF-κB signaling pathway is central to the innate and adaptive immune responses. Upon their detection of pathogen-associated molecular patterns, Toll-like receptors on the cell surface initiate signal transduction and activate the NF-κB pathway, leading to the production of a wide array of inflammatory cytokines, in attempt to eradicate the invaders. As a countermeasure, pathogens have evolved ways to subvert and manipulate this system to their advantage. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) are closely related bacteria responsible for major food-borne diseases worldwide. Via a needle-like protein complex called the type three secretion system (T3SS), these pathogens deliver virulence factors directly to host cells and modify cellular functions, including by suppressing the inflammatory response. Using gain- and loss-of-function screenings, we identified two bacterial effectors, NleC and NleE, that down-regulate the NF-κB signal upon being injected into a host cell via the T3SS. A recent report showed that NleE inhibits NF-κB activation, although an NleE-deficient pathogen was still immune-suppressive, indicating that other anti-inflammatory effectors are involved. In agreement, our present results showed that NleC was also required to inhibit inflammation. We found that NleC is a zinc protease that disrupts NF-κB activation by the direct cleavage of NF-κB's p65 subunit in the cytoplasm, thereby decreasing the available p65 and reducing the total nuclear entry of active p65. More importantly, we showed that a mutant EPEC/EHEC lacking both NleC and NleE (ΔnleC ΔnleE) caused greater inflammatory response than bacteria carrying ΔnleC or ΔnleE alone. This effect was similar to that of a T3SS-defective mutant. In conclusion, we found that NleC is an anti-inflammatory bacterial zinc protease, and that the cooperative function of NleE and NleC disrupts the NF-κB pathway and accounts for most of the immune suppression caused by EHEC/EPEC.

Dataset Information

HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-?B and depends on chronically activated IKK? and p65/RelA.

Publications

HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-κB and depends on chronically activated IKKα and p65/RelA.

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