Abstract
Expression of xCT, a component of the xc– amino-acid transporter, is essential for the uptake of cystine required for intracellular glutathione (GSH) synthesis and maintenance of the intracellular redox balance. Therefore, xCT plays an important role not only in the survival of somatic and immune cells, but also in other aspects of tumorigenesis, including the growth and malignant progression of cancer cells, resistance to anticancer drugs, and protection of normal cells against oxidative damage induced by carcinogens. xCT also functions as a factor required for infection by Kaposi’s sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi’s sarcoma (KS) and other lymphoproliferative diseases associated with HIV/AIDS. In spite of these advances, our understanding of the role of xCT in the pathogenesis of infectious diseases is still limited. Therefore, this review will summarize recent findings about the functions of xCT in diseases associated with microbial (bacterial or viral) infections, in particular KSHV-associated malignancies. We will also discuss the remaining questions, future directions, as well as evidence that supports the potential benefits of exploring system xc– as a target for prevention and clinical management of microbial diseases and cancer.
Highlights
The xc− amino-acid transporter, consisting of xCT and its chaperone CD98, functions as a Na+-independent electroneutral exchange system for cystine/glutamate (Bannai and Kitamura, 1980)
We and others recently reported the functional contributions of xCT to the pathogenesis of Kaposi’s sarcomaassociated herpesvirus (KSHV; Kaleeba and Berger, 2006a,b; Qin et al, 2010b, 2013; Dai et al, 2014a), a principal causative agent of several cancers arising in patients with compromised immune systems (Chang et al, 1994)
CONCLUDING REMARKS In contrast to extensive studies of the role of xCT as an amino-acid transporter involved in the survival of normal and cancer cells, there are very limited data describing its role in microbial infection and/or the pathogenesis of associated diseases
Summary
The xc− amino-acid transporter, consisting of xCT ( named as SLC7A11) and its chaperone CD98, functions as a Na+-independent electroneutral exchange system for cystine/glutamate (Bannai and Kitamura, 1980). Expression of xCT on the cell membrane is essential for the uptake of cystine required for synthesis of intracellular glutathione (GSH), an anti-oxidant that plays an important role in maintaining the intracellular redox balance (Bannai, 1986; Patel et al, 2004). XCT is involved in other important cellular functions within cancer cells, such as chemoresistance (Okuno et al, 2003; Huang et al, 2005) and autophagy (Guo et al, 2011). We and others recently reported the functional contributions of xCT to the pathogenesis of Kaposi’s sarcomaassociated herpesvirus (KSHV; Kaleeba and Berger, 2006a,b; Qin et al, 2010b, 2013; Dai et al, 2014a), a principal causative agent of several cancers arising in patients with compromised immune systems (Chang et al, 1994). In light of the emerging pleiotropic functions of xCT, the goal of this review is to summarize recent findings about the role of xCT in microbial infection and associated diseases ( virus-associated malignancies), and to discuss potential future directions for research in this particular field
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