xCT, not just an amino-acid transporter: a multi-functional regulator of microbial infection and associated diseases

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.

Mechanisms of ferroptosis

“…This may be beneficial if the goal is to trigger an immune response. Interestingly, the system transporter SLC7A11 is required for entry of Kaposi’s sarcoma-associated herpesvirus into certain cells [ 82 ], a process likely to disrupt normal glutathione homeostasis. Likewise infection of immune cells with the human immunodeficiency virus type-1 (HIV-1) is well know to cause dysregulation of glutathione homeostasis [ 83 , 84 ], possibly enhancing sensitivity to ferroptosis.…”

The cystine‐glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain

“…As induction of xCT has been reported in response to a number of different stimuli (for review see Bridges R J et al, ; Lewerenz et al, ; Dai, Noverr, Parsons, Kaleeba, & Qin, ; Massie et al, ), the possibility exists that other cell types than astrocytes, microglia in particular, may under certain conditions start expressing xCT. Most evidence for microglial xCT expression comes from in vitro studies, but there are some reports on induced xCT expression in reactive microglia in vivo (for references see: Bentea et al, ).…”

Diabetes and risk of Kaposi's sarcoma: effects of high glucose on reactivation and infection of Kaposi's sarcoma-associated herpesvirus

“…Additionally, several lines of evidence revealed that the temporal interaction between integrins α3β1 and xCT/CD98 is relevant to cell adhesion, fusion, proliferation and the integrin-dependent signal transduction [ 26 , 35 ]. Noteworthily, the xCT/CD98 complex, a cystine/glutamate exchange transporter, naturally functions to maintain the intracellular redox balance and protects cells from death induced by oxidative stress [ 35 , 36 ]. Based on the mentioned roles of integrins α3β1 and xCT/CD98 in cells, we therefore propose that elevated levels of integrin α3β1 and xCT/CD98 in endothelial and epithelial cells caused by high glucose may facilitate subsequent KSHV infection.…”