ASCT2 (SLC1A5)-Deficient Mice Have Normal B-Cell Development, Proliferation, and Antibody Production

Abstract

SLC1A5 (solute carrier family 1, member 5) is a small neutral amino acid exchanger that is upregulated in rapidly proliferating lymphocytes but also in many primary human cancers. Furthermore, cancer cell lines have been shown to require SLC1A5 for their survival in vitro. One of SLC1A5’s primary substrates is the immunomodulatory amino acid glutamine, which plays an important role in multiple key processes, such as energy supply, macromolecular synthesis, nucleotide biosynthesis, redox homeostasis, and resistance against oxidative stress. These processes are also essential to immune cells, including neutrophils, macrophages, B and T lymphocytes. We show here that mice with a stop codon in Slc1a5 have reduced glutamine uptake in activated lymphocytes and primary fibroblasts. B and T cell populations and maturation in resting mice were not affected by absence of SLC1A5. Antibody production in resting and immunized mice and the germinal center response to immunization were also found to be normal. SLC1A5 has been recently described as a novel target for the treatment of a variety of cancers, and our results indicate that inhibition of SLC1A5 in cancer therapy may be tolerated well by the immune system of cancer patients.

Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice

“…4h ). Glutamine is predominantly transported by system ASC (SLC1A4 and SLC1A5) and system A and N (SLC38A1, SLC38A2, SLC38A5 and SLC38A7) transporters 27 , 28 . Quantitative proteomics data showed that the predominant glutamine transporters in activated NK cells are SLC1A5 and SLC38A2 (Supplementary Fig.…”

A central role of glutamine in Chlamydia infection

“…Recently, SLC1A5 knockout mice have been generated (Supplementary Fig. 6c), which show no major phenotype 25 . Interestingly, trans-cervical infection of these mice revealed a significant growth defect of Chlamydia in the absence of SLC1A5 compared to control (Fig.…”

“…In addition, chlamydial growth was severely affected in genital infections of ASCT2/SLC1A5 knockout mice. This first demonstration of a dominant role of host cell glutamine reprogramming in an in vivo infection at all was surprising since this knockout mouse has no other major phenotype 25 . Gln is channeled into different anabolic and catabolic pathways by glutaminolysis, generating Glu and subsequently α-KG, both of which are essential for infection and replication of several viruses 31–36 .…”

“…ASCT2/SLC1A5 KO mice generated in a C57BL/6 background were obtained from the Australian National University (ANU) 25 . All animal experiments were performed in accordance with protocols approved by animal care and experimentation of German Animal Protection Law approved under the Animal (Scientific Procedures) Act 1986 (project license 55.2-2532-2-762).…”

Homology Modeling Informs Ligand Discovery for the Glutamine Transporter ASCT2

“…Previous studies have shown that knock down of ASCT2 results in tumor growth attenuation in vitro (Nicklin et al, 2009 ; Wang et al, 2014 , 2015 ; van Geldermalsen et al, 2016 ; Schulte et al, 2018 ) and in vivo (Wang et al, 2015 ; van Geldermalsen et al, 2016 ), and the viability of ASCT2 knockout mice suggests that pharmacological targeting of ASCT2 may not affect normal cells (Nakaya et al, 2014 ; Masle-Farquhar et al, 2017 ). Indeed, a recent study showed that pharmacological inhibition of ASCT2 reduced cancer cell growth and proliferation in vitro and in vivo (Schulte et al, 2018 ).…”