CLIC4, a multifunctional protein that traffics between the cytoplasm and nucleus, interacts with Schnurri-2, a transcription factor in the BMP pathway. TGF-β enhances the expression of both CLIC4 and Schnurri-2 and promotes their association in the cytoplasm and their translocation to the nucleus. In the absence of CLIC4 or Schnurri-2, TGF-β signalling is abrogated. Direct nuclear targeting of CLIC4 enhances TGF-β signalling and removes the requirement for Schnurri-2. Nuclear CLIC4 associates with phospho-Smad2 and 3 and protects them from dephosphorylation by nuclear phosphatases. An intact TGF-β signalling pathway is essential for CLIC4 to mediate growth arrest. These results reveal Schnurri-2 and CLIC4 as previously unidentified modifiers of TGF-β signalling through stabilizing phospho-Smad2 and phospho-Smad3 in the nucleus.

Immune activation plays an important role in the pathogenesis of HIV disease. Although the causes are not fully understood, the forces that lead to immune dysfunction differ for CD4 and CD8 T cells. In this study, we report that the molecular pathways that drive immune activation during chronic HIV infection are influenced by differences in the homeostatic regulation of the CD4 and CD8 T cell pools. Proliferation of CD4 T cells is controlled more tightly by CD4 T cell numbers than is CD8 T cell proliferation. This difference reflects the importance of maintaining a polyclonal CD4 T cell pool in host surveillance. Both pools of T cells were found to be driven by viral load and its associated state of inflammation. In the setting of HIV-induced lymphopenia, naive CD4 T cells were recruited mainly into the proliferating pool in response to CD4 T cell depletion, whereas naive CD8 T cell proliferation was driven mainly by levels of HIV RNA. RNA analysis revealed increased expression of genes associated with type I IFN and common γ chain cytokine signaling in CD4 T cell subsets and only type I IFN-associated genes in CD8 T cell subsets. In vitro studies demonstrated enhanced STAT1 phosphorylation in response to IFN-α and increased expression of the IFNAR1 transcripts in naive and memory CD4 T cells compared with that observed in CD8 T cells. CD4 T cell subsets also showed enhanced STAT1 phosphorylation in response to exogenous IL-7.

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