HDAC6 mediates HIV-1 tat-induced proinflammatory responses by regulating MAPK-NF-kappaB/AP-1 pathways in astrocytes

De novo synthesized IkappaBalpha accumulates transiently in the nucleus where it inhibits NF-kappaB-dependent transcription and reduces nuclear NF-kappaB content. A sequence present in the C-terminal domain of IkappaBalpha and homologous to the HIV-1 Rev nuclear export signal (NES) has been recently defined as a functional NES conferring on IkappaBalpha the ability to export IkappaBalpha/NF-kappaB complexes. Rev utilises its RNA-binding activity and NES sequence to promote specifically the transport of unspliced and monospliced viral RNAs to the cytoplasm. The object of this work was to determine if nuclear IkappaBalpha could interfere with Rev-dependent transport of viral RNA from the nucleus to the cytoplasm. We report that accumulation of IkappaBalpha in the cell nucleus blocks viral replication. This effect could be dissociated from the capacity of IkappaBalpha to inhibit NF-kappaB-DNA-binding activity and required a functional IkappaBalpha NES motif. Indeed, mutation of the NES abrogated the capacity of IkappaBalpha to inhibit Rev-dependent mechanisms involved in the replication of either wild-type or NF-kappaB-mutated HIV-1 molecular clones. Nuclear accumulation of a reporter protein tagged with a nuclear localization signal (NLS) and fused to the IkappaBalpha NES motif (NLS-PK-NES) was sufficient to inhibit HIV-1 replication at a post-transcriptional level by specifically blocking the expression of a Rev-dependent gene. Furthermore, in cells pulsed with TNF, a treatment which favors nuclear accumulation of newly synthesized IkappaBalpha, NLS-PK-NES expression promoted sustained accumulation of nuclear NF-kappaB lacking DNA-binding activity. This NES-mediated accumulation of inactive nuclear NF-kappaB is likely the consequence of interference in the IkappaBalpha-mediated export of NF-kappaB. These findings indicate that IkappaBalpha and Rev compete for the same nuclear export pathway and suggest that nuclear accumulation of IkappaBalpha, which would occur during normal physiological cell activation process, may interfere with the Rev-NES-mediated export pathway of viral RNAs, thus inhibiting HIV-1 replication.

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Abstract 563: Oxidized LDL Promotes Endothelial NF-kappaB Activation and Inflammation Through Focal Adhesion Kinase-dependent RSK Signaling

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.563 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Arif Yurdagul ◽

Christopher B Pattillo ◽

David D Schlaepfer ◽

Wayne Orr

Keyword(s):

Gene Expression ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Oxidized Ldl ◽

Monocyte Adhesion ◽

Proinflammatory Responses ◽

Proinflammatory Gene ◽

Ribosomal S6 Kinase ◽

Nf Kappab ◽

Proinflammatory Gene Expression

Oxidized LDL (oxLDL) accumulates early in atherosclerosis and promotes endothelial NF-kappaB activation, proinflammatory gene expression, and monocyte adhesion. Like other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-kappaB signaling has yet to be revealed. We now show that oxLDL induces NF-kappaB activation and VCAM-1 expression through FAK-dependent IkappaB kinase beta (IKKbeta) activation. We further identify FAK-dependent activation of p90 ribosomal S6-kinase (RSK) as a critical mediator of oxLDL-dependent IKKbeta/NF-kappaB signaling, as inhibiting RSK blocks oxLDL-induced IKKbeta/NF-kappaB activation, VCAM-1 expression, and monocyte adhesion. Lastly, transgenic mice containing a kinase-dead mutation in FAK specifically in the endothelial cells show reduced RSK activity, decreased VCAM-1 expression, and reduced macrophage accumulation in regions of early atherosclerosis. Taken together, our data elucidates a novel mechanism whereby oxLDL-induced endothelial FAK signaling drives an ERK/RSK pathway to activate IKKbeta/NF-kappaB signaling and proinflammatory gene expression.

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Infection of human immunodeficiency virus 1 transgenic mice with Toxoplasma gondii stimulates proviral transcription in macrophages in vivo.

Journal of Experimental Medicine ◽

10.1084/jem.183.4.1645 ◽

1996 ◽

Vol 183 (4) ◽

pp. 1645-1655 ◽

Cited By ~ 42

Author(s):

R T Gazzinelli ◽

A Sher ◽

A Cheever ◽

S Gerstberger ◽

M A Martin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Toxoplasma Gondii ◽

Transgenic Mice ◽

Transgenic Mouse ◽

Ex Vivo ◽

Mouse Strains ◽

Immunodeficiency Virus ◽

Nf Kappab ◽

Hiv 1

Human immunodeficiency virus (HIV) 1 transgenic mice expressing low or undetectable levels of viral mRNA in lymphoid tissue were infected with the intracellular protozoan Toxoplasma gondii. Exposure to this parasite resulted in an increase in HIV-1 transcript in lymph nodes, spleens, and lungs during the acute phase of infection and in the central nervous system during the chronic stage of disease. In vivo and ex vivo experiments identified macrophages as a major source of the induced HIV-1 transcripts. In contrast, T. gondii infection failed to stimulate HIV-1 transcription in tissues of two HIV-1 transgenic mouse strains harboring a HIV-1 proviral DNA in which the nuclear factor (NF) kappa B binding motifs from the viral long terminal repeats had been replaced with a duplicated Moloney murine leukemia virus core enhancer. A role for NF-kappaB in the activation of the HIV-1 by T. gondii was also suggested by the simultaneous induction of NF-kappaB binding activity and tumor necrosis factor alpha synthesis in transgenic mouse macrophages stimulated by exposure to parasite extracts. These results demonstrate the potential of an opportunistic pathogen to induce HIV-1 transcription in vivo and suggest a mechanism for the in vivo dissemination of HIV-1 by macrophages.

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