Activation of Transcription Factor Nrf-2 and Its Downstream Targets in Response to Moloney Murine Leukemia Virusts1-Induced Thiol Depletion and Oxidative Stress in Astrocytes

Abstract

The neuroimmunodegenerative syndrome that develops in mice infected with ts1, a mutant of Moloney murine leukemia virus, resembles human AIDS. Both ts1 and human immunodeficiency virus type 1 infect astrocytes, microglia, and oligodendrocytes but do not infect neurons. Oxidative stress has been implicated in the neuropathology of AIDS dementia and other neurodegenerative diseases. We report here that ts1 infection of astrocytes (both transformed C1 cells and primary cultures) also induces thiol (i.e., glutathione and cysteine) depletion and reactive oxygen species (ROS) accumulation, events occurring in parallel with viral envelope precursor gPr80(env) accumulation and upregulated expression of endoplasmic reticulum chaperones GRP78 and GRP94. Furthermore, ts1-infected astrocytes mobilize their thiol redox defenses by upregulating levels of the Nrf-2 transcription factor, as well its targets, the xCT cystine/glutamate antiporter, gamma-glutamylcysteine ligase, and glutathione peroxidase. Depleting intracellular thiols by treating uninfected astrocytes with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, or by culturing in cystine-deficient medium, also induces ROS accumulation, activates Nrf-2, and upregulates Nrf-2 target gene expression in these astrocytes. Overexpression of Nrf-2 in astrocytes specifically increases expression of the above thiol synthesis-related proteins. Further treatment with BSO or N-acetylcysteine in transfected cells modulates this expression. Thiol depletion also accelerates cell death, while thiol supplementation promotes survival of ts1-infected cells. Together, our results indicate that ts1 infection of astrocytes, along with ts1-induced gPr80(env) accumulation, endoplasmic reticulum stress, thiol depletion, and oxidative stress, accelerates cell death; in response to the thiol depletion and oxidative stress, astrocytes activate their Nrf-2-mediated thiol antioxidant defenses, promoting cell survival.

Activation of transcription factor Nrf2 by hepatitis C virus induces the cell-survival pathway

“…We observed that HCV infection can induce and translocate Nrf2 in a time-dependent manner, and demonstrated further that HCV-induced Nrf2 activation is sensitive to antioxidants and Ca 2+ chelators. This is consistent with previous observations that, in response to virus infection, activation of Nrf2 occurs under conditions of oxidative stress (Qiang et al, 2004;Jiang et al, 2006).…”

“…Recently, it has been shown that upregulation of Nrf2 in lung cancer cells stimulated growth of lung cancerderived cell lines (Padmanabhan et al, 2006;Ohta et al, 2008). Previous studies have demonstrated that Nrf2 in Moloney murine leukemia virus ts1-infected astrocytes was activated in response to thiol depletion and oxidative stress (Qiang et al, 2004). Oxidative and electrophilic stresses are the major stimuli that provoke the induction of Nrf2 target genes (Ohta et al, 2008).…”

ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

“…22,38 Here, we have shown that levels of ER stress markers, GRP78 and cleavage of procaspase-12 were also increased in Atm À/À astrocytes (Figure 3a).…”

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

“…Recent studies indicate that Syncytin-1 transcript levels are quantitatively increased in the brains of MS patients compared with other inflammatory neurological disease controls (10). Interestingly, TNF-␣, an inflammatory molecule in the brains of MS patients, was found to enhance Syncytin-1 expression in astrocytes (11), which consequently results in production of free radicals and cytokines (12) that could affect expression of ASCT1 and ASCT2, given that free radicals influence expression of membrane proteins (13,14). Free radicals are also produced when cells undergo persistent endoplasmic reticulum (ER) stress (15), a constellation of host responses, which maintain cellular homeostasis, termed the unfolded protein response (16).…”