Zinc: A Potential Antiviral Against Hepatitis E Virus Infection?

Hepatitis E virus (HEV) is a major cause of viral hepatitis worldwide. Owing to its feco oral transmission route, sporadic as well as epidemic outbreaks recurrently occur. No specific antiviral therapy is available against the disease caused by HEV. Broad spectrum antivirals such as ribavirin and interferon alfa are prescribed in severe and chronic HEV cases. However, the side effects, cost, and limitations of usage render the available treatment unsuitable for several categories of patients. We recently reported the ability of zinc to inhibit viral replication in mammalian cell culture models of HEV infection. Zinc will be a safe and economical antiviral therapy option if it inhibits HEV replication during the natural course of infection. This essay discusses the putative mechanism(s) by which zinc inhibits HEV replication and provides an overview of the possible therapeutic potential of zinc in HEV patients.

Similarities and differences in the transcriptional control of expression of the mouse TSLP gene in skin epidermis and intestinal epithelium.

We previously reported that selective ablation of the nuclear receptors retinoid X receptor (RXR)-α and RXR-ß in mouse epidermal keratinocytes (RXR-αßep-/-) or a topical application of active vitamin D3 (VD3) and/or all-trans retinoic acid (RA) on wild-type mouse skin induces a human atopic dermatitis-like phenotype that is triggered by an increased expression of the thymic stromal lymphopoietin (TSLP) proinflammatory cytokine. We demonstrate here that in epidermal keratinocytes, unliganded heterodimers of vitamin D receptor (VDR)/RXR-α and retinoic acid receptor-γ (RAR-γ)/RXR-ß are bound as repressing complexes to their cognate DNA-binding sequence(s) (DBS) in the TSLP promoter regulatory region. Treatments with either an agonistic VD3 analog or RA dissociate the repressing complexes and recruit coactivator complexes and RNA polymerase II, thereby inducing transcription. Furthermore, we identified several functional NF-κB, activator protein 1 (AP1), STAT, and Smad DBS in the TSLP promoter region. Interestingly, many of these transcription factors and DBS present in the TSLP promoter region are differentially used in intestinal epithelial cell(s) (IEC). Collectively, our study reveals that, in vivo within their heterodimers, the RXR and RAR isotypes are not functionally redundant, and it also unveils the combinatorial mechanisms involved in the tissue-selective regulation of TSLP transcription in epidermal keratinocytes and IEC.

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex.

Upon binding of a glucocorticoid (GC), the GC receptor (GR) can exert one of three transcriptional regulatory functions. We recently reported that SUMOylation of the GR at position K293 in humans (K310 in mice) within the N-terminal domain is indispensable for GC-induced evolutionary conserved inverted repeated negative GC response element (IR nGRE)-mediated direct transrepression. We now demonstrate that the integrity of this GR SUMOylation site is mandatory for the formation of a GR-small ubiquitin-related modifiers (SUMOs)-SMRT/NCoR1-HDAC3 repressing complex, which is indispensable for NF-κB/AP1-mediated GC-induced tethered indirect transrepression in vitro. Using GR K310R mutant mice or mice containing the N-terminal truncated GR isoform GRα-D3 lacking the K310 SUMOylation site, revealed a more severe skin inflammation than in WT mice. Importantly, cotreatment with dexamethasone (Dex) could not efficiently suppress a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in these mutant mice, whereas it was clearly decreased in WT mice. In addition, in mice selectively ablated in skin keratinocytes for either nuclear receptor corepressor 1 (NCoR1)/silencing mediator for retinoid or thyroid-hormone receptors (SMRT) corepressors or histone deacetylase 3 (HDAC3), Dex-induced tethered transrepression and the formation of a repressing complex on DNA-bound NF-κB/AP1 were impaired. We previously suggested that GR ligands that would lack both (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression activities of GCs may preferentially exert the therapeutically beneficial GC antiinflammatory properties. Interestingly, we now identified a nonsteroidal antiinflammatory selective GR agonist (SEGRA) that selectively lacks both Dex-induced (+)GRE-mediated transactivation and IR nGRE-mediated direct transrepression functions, while still exerting a tethered indirect transrepression activity and could therefore be clinically lesser debilitating on long-term GC therapy.

Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor.

The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex "negative" GREs (nGREs) has been reported. However, GR-mediated transrepression was generally ascribed to indirect "tethered" interaction with other DNA-bound factors. We report that GC-induces direct transrepression via the binding of GR to simple DBS (IR nGREs) unrelated to (+)GRE. These DBS act on agonist-liganded GR, promoting the assembly of cis-acting GR-SMRT/NCoR repressing complexes. IR nGREs are present in over 1000 mouse/human ortholog genes, which are repressed by GC in vivo. Thus variations in the levels of a single ligand can coordinately turn genes on or off depending in their response element DBS, allowing an additional level of regulation in GR signaling. This mechanism suits GR signaling remarkably well, given that adrenal secretion of GC fluctuates in a circadian and stress-related fashion.