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A look into the testis as a reservoir for HIV and ZIKV—A reproductive biologist’s perspective
Published in C. Yan Cheng, Spermatogenesis, 2018
Elizabeth I. Tang, Christopher L. Robinson, Chi Nok Chong, Shuibing Chen, C. Yan Cheng
Finding a suitable model to study ZIKV has proven challenging. To date, a small number of studies investigating the role of ZIKV and its consequences in the male reproductive tract have emerged. In humans, ZIKV targets transcription factor STAT2 and initiates its degradation, disrupting type I IFN signaling.73,74 However, when wild-type (WT) mice, a typical study model, were infected with ZIKV they were found to have little or no infectious virus/viral RNA in their tissues.71 Interestingly, ZIKV does not target STAT2 in WT mice, which may be one of the reasons why WT mice are resistant to ZIKV infection.71,73,74 Due to the general resistance of immunocompetent mice to ZIKV, scientists have used other approaches to establish a working ZIKV mouse model.
Virus Wars
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Markus Vähä-Koskela, Fabrice Le Boeuf, Vincenzo Cerullo
In addition to proteasomal degradation, several signaling components of antiviral and proinflammatory pathways are targeted for inhibition by the V protein of other paramyxovirus members. Measles virus V protein binds to and inhibits nuclear translocation of STAT-2 and STAT-1 in a STAT-2-dependent manner (Chinnakannan et al. 2013; Palosaari et al. 2003; Ramachandran et al. 2008). In doing so, it inhibits signaling via type I and type II IFN receptors. In addition to STAT-2, V protein of measles virus specifically binds to the Relhomology domain of the NF-κB subunit p65, as well as to interferon regulatory factor 7 (IRF7), and melanoma differentiation-associated protein 5 (MDA5) significantly inhibiting type I IFN-independent interferon-stimulated gene (ISG) activation and nuclear factor kappa-light-chain-enhancer of activated B cells (NfκB)-dependent proinflammatory cytokine expression (Schuhmann et al. 2011). Another oncolytic virus featuring multiple anti-inflammatory mechanisms is vaccinia virus (e.g., scavenger receptors against type I and type II IFNs, IL-1β, and several chemokines) (Turner and Moyer 2002); overall, the role of targeting the inflammatory cascades by oncolytic viruses in treatment of oncovirus-associated tumors (where the oncovirus itself may drive similar anti-inflammatory functions) is unclear.
Alphavirus Neurovirulence
Published in Sunit K. Singh, Daniel Růžek, Neuroviral Infections, 2013
Katherine Taylor, Slobodan Paessler
Comparison of both naturally and experimentally attenuated viruses to virulent strains has generated valuable knowledge regarding the basis for IFN resistance and subsequent neurovirulence. Priming neurons with IFN before infection with either VEEV or SINV further demonstrates VEEV’s resistance to an established antiviral state compared with SINV as VEEV continues to replicate and produce progeny virion in primed cells in contrast to more sensitive SINV. VEEV resistance was attributed to partial blockade of phosphorylation of IFN signaling pathway molecules, STAT1 and STAT2, mediated by expression of nonstructural proteins. VEEV also inhibits interferon signaling genes (ISG) through structural protein expression (Yin et al. 2009).
Zika virus pathogenesis and current therapeutic advances
Published in Pathogens and Global Health, 2021
Caroline Mwaliko, Raphael Nyaruaba, Lu Zhao, Evans Atoni, Samuel Karungu, Matilu Mwau, Dimitri Lavillette, Han Xia, Zhiming Yuan
The NS5 protein is the largest (approximately 900 amino acids) and most conserved of the flavivirus proteins. The NS5 protein contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis [60]. NS5 is also an IFN antagonist that degrades STAT2, which in turn, limits type I IFN signaling and leads to increased viral replication. STAT2 is a signaling molecule required in the IFN I pathway. The mechanism of STAT2 degradation in ZIKV by the NS5 protein is distinct from that in DENV. Expression of ZIKV NS5 alone results in STAT 2 degradation and does not require maturation of the N terminus of NS5 and does not involve UBR4 [61]. The interaction is also host-specific since NS5 is unable to degrade murine STAT2, leading to susceptibility to ZIKV infection in immunocompetent mice. ZIKV has been shown to bind and degrade STAT2 through proteasomal degradation. Antagonism of STAT1 and STAT2 phosphorylation results in ZIKV disease [62].
Progesterone receptor promotes degradation of STAT2 to inhibit the interferon response in breast cancer
Published in OncoImmunology, 2020
Katherine R. Walter, Justin M. Balko, Christy R. Hagan
Much of the current knowledge regarding interferon signaling has focused on the role of STAT1, as it is a major component of multiple interferon-regulated transcriptional complexes. Emerging data, however, has illuminated the essential role for STAT2 in promotion of type I interferon signaling during viral infection.25,26 The dependence on STAT2 to propagate the immune response in breast cancer, however, has been understudied. To tease apart how loss of STAT proteins affect ISGF3 component DNA binding, we first utilized T47D cells stably expressing either non-silencing (NS) or STAT1 shRNA (mRNA to confirm STAT1 knockdown with shRNA shown in Figure 3(a), protein in Figure 5(b)). Using chromatin immunoprecipitation (ChIP) assays, we found that in cells lacking STAT1, STAT2, and IRF9 were still able to bind DNA at Interferon Stimulated Gene (ISG) promoters (ISREs) in response to IFNα (Figure 3(b), Supplementary Table 3); recruitment at select representative ISGs is shown. To then test the dependence upon STAT2, we used shRNA to stably knockdown STAT2 (mRNA shown in Figure 4(a), protein in Figure 5(b)). Contrary to what occurred when STAT1 was knocked down, we observed abrogated recruitment of STAT1 and IRF9 to ISG promoters, suggesting STAT2 is necessary to promote efficient DNA binding of other ISGF3 components (Figure 4(b), Supplementary Table 4). These data suggest that STAT2, not STAT1, is essential in mediating the interferon response.
Inhibition of MEK with trametinib enhances the efficacy of anti-PD-L1 inhibitor by regulating anti-tumor immunity in head and neck squamous cell carcinoma
Published in OncoImmunology, 2019
Seong-Ho Kang, Bhumsuk Keam, Yong-Oon Ahn, Ha-Ram Park, Miso Kim, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo
Next, we investigated the effects of trametinib on STAT signaling pathway, as it is known to regulate MHC class I and/or PD-L1 expression.29–32 First, we confirmed that trametinib suppresses Erk1/2 phosphorylation at a concentration of 50 nM we used (Supplementary Fig. S1A). When we assessed change in STAT phosphorylation upon trametinib and IFN-γ treatment, except for STAT4, whose expression is restricted to myeloid cells, thymus and testes, we found that treatment with trametinib increased p-STAT1 expression, and this effect was enhanced in the presence of exogenous IFN-γ (Figure 2A). While total STAT1 expression was low, expression was increased after IFN-γ treatment, via input from a positive feedback loop, and this was further enhanced by trametinib in some cells. Furthermore, trametinib treatment activated STAT3 and STAT6 was shown to be activated by trametinib treatment in three of six cell lines. Phosphorylated STAT2 and STAT5 were not detected in any condition of any cell line we used (data not shown).