Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-α inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-α levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-α production does occur

HDM2 negatively affects the Chk2-mediated phosphorylation of p53

AbstractBy GST pull downs and co-immunoprecipitation analyses we found that recombinant Chk2 and HDM2 can form stable complexes in vitro. Chk2/HDM2 complexes were also detected in transfected Cos-1 cells over-expressing both proteins. Furthermore, we show that HDM2, as would be expected, severely affects the Chk2-catalyzed phosphorylation of p53. HDM2 itself is only slightly phosphorylated by Chk2. However, whereas HDM2 inhibits the Chk2-catalyzed p53 phosphorylation, HDM2 phosphorylation by Chk2 doubles in the presence of p53. The significance of the HDM2 phosphorylation is unknown, but it is possible that it might influence the stability of the HDM2/p53 complex

Casein kinase 2β as a novel enhancer of activin-like receptor-1 signaling

ALK-1 is a transforming growth factor β (TGF-β) superfamily receptor that is predominantly expressed in endothelial cells and is essential for angiogenesis, as demonstrated by the embryonic lethal phentoype when targeted for deletion in mice and its mutation in the human disease hereditary hemorrhagic telangiectasia. Although ALK-1 and the endothelial-specific TGF-β superfamily coreceptor, endoglin, form a heteromeric complex and bind similar TGF-β superfamily ligands, their signaling mechanisms remain poorly characterized. Here we report the identification of CK2β, the regulatory subunit of protein kinase CK2, as a novel enhancer of ALK-1 signaling. The cytoplasmic domain of ALK-1 specifically binds to CK2β in vitro and in vivo. NAAIRS mutagenesis studies define amino acid sequences 181–199 of CK2β and 207–212 of ALK-1 as the interaction domains, respectively. The ALK-1/CK2β interaction specifically enhanced Smad1/5/8 phosphorylation and ALK-1-mediated reporter activation in response to TGF-β1 and BMP-9 treatment. In a reciprocal manner, siRNA-mediated silencing of endogenous CK2β inhibited TGF-β1 and BMP-9-stimulated Smad1/5/8 phosphorylation and ALK-1-mediated reporter activation. Functionally, CK2β enhanced the ability of activated or ligand-stimulated ALK-1 to inhibit endothelial cell migration. Similarly, ALK-1 and CK2β antagonized endothelial tubule formation in Matrigel. These studies support CK2β as an important regulator of ALK-1 signaling and ALK-1-mediated functions in endothelial cells.—Lee, N. Y., Haney, J. C., Sogani, J., Blobe, G. C. Casein kinase 2β as a novel enhancer of activin-like receptor-1 signaling

Crystallization and preliminary X-ray crystallographic analysis of human FAF1 UBX domain

The FAF1 UBX domain was crystallized. X-ray diffraction data were collected to 3.00 Å resolution and the crystals belonged to space group F4132