| 8.A.9 The rBAT Transport Accessory Protein (rBAT) Family
The rBAT (related to b0,+ amino acid transport) proteins have been sequenced from a variety of animals and when expressed in frog oocytes, they cause induction of cationic and neutral amino acid uptake. The ancillary proteins of the SLC3 family of amino acid transporters are esstenial for amino acid transport via the heteromeric SLC7 carriers (Palacín and Kanai 2004). The activities enhanced depend on the cell type. The rBAT and homologous 4F2hc proteins, which like rBAT proteins, stimulate amino acid transport, have 520-690 amino acids and are glycoproteins with a putative hydrophobic TMS and possibly as many as three additional amphipathic TMSs. These proteins are homologous to maltases, α-glucosidases and trehalose 6-P hydrolases. They are probably auxiliary proteins that are required for insertion of or stimulation of the activities of various porters, including some of those of the APC family (TC# 2.A.3). Some of these homologues have been shown to associate with various amino acid porters to form heterodimeric or heterotetrameric protein complexes. Computational analyses have identifies druggable mutations in human rBAT that mediate Cystinuria (Pandey et al. 2020).
The 4F2hc protein is called the cell surface antigen heavy chain, lymphocyte activation antigen and CD98. It activates the cystine/glutamate antiporter (2.A.3.8.5) and other amino acid transporters (Sato et al., 2005). CD98 in intestinal epithelia is an oligomeric and multifunctional protein (Yan et al., 2008). For 4F2hc, functional interaction with LAT1 is mediated by the N-terminal part, comprising the cytoplasmic tail, transmembrane segment and neck, in the absence of the extracellular domain. However, functional association with LAT1 is also supported by the extracellular part of 4F2hc comprising the neck and glycosidase-like domains linked to the complementary part of rBAT (Franca et al. 2005). The ectodomains of rBAT and 4F2hc are fake or non-functional α-glucosidases (Fort et al. 2021).
rBAT dictates oligomerization of heteromeric amino acid transporters. For example, system b0,+ is a heterotetramer (b0,+AT-rBAT)2 as is system xC- (xCT-rBAT)2 although xCT-4F2hc does not effectively oligomerize (Fernandez et al., 2006). Nevertheless, a single heterodimer is the functional unit in all cases. The cytoplasmic tail and transmembrane domain of rBAT together play a dominant role in selective functional interaction with b(0,+)AT, whereas the extracellular domain of rBAT appears to facilitate specifically L-cystine uptake (Franca et al. 2005).
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| References: |
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Baumer, Y., S. McCurdy, M. Alcala, N. Mehta, B.H. Lee, M.H. Ginsberg, and W.A. Boisvert. (2017). CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis. Atherosclerosis 256: 105-114.
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Console, L., M. Scalise, S. Salerno, R. Scanga, D. Giudice, L. De Bartolo, A. Tonazzi, and C. Indiveri. (2022). N-glycosylation is crucial for trafficking and stability of SLC3A2 (CD98). Sci Rep 12: 14570.
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Cui, Y., L. Qin, D. Tian, T. Wang, L. Fan, P. Zhang, and Z. Wang. (2018). ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2. Chemotherapy 63: 262-271.
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Digomann, D., A. Linge, and A. Dubrovska. (2019). SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed. Autophagy 15: 1850-1851.
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Estrach S., Lee SA., Boulter E., Pisano S., Errante A., Tissot FS., Cailleteau L., Pons C., Ginsberg MH. and Feral CC. (2014). CD98hc (SLC3A2) loss protects against ras-driven tumorigenesis by modulating integrin-mediated mechanotransduction. Cancer Res. 74(23):6878-89.
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Foley, M.H., E.C. Martens, and N.M. Koropatkin. (2018). SusE facilitates starch uptake independent of starch binding in B. thetaiotaomicron. Mol. Microbiol. 108: 551-566.
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Fort, J., A. Nicolàs-Aragó, and M. Palacín. (2021). The Ectodomains of rBAT and 4F2hc Are Fake or Orphan α-Glucosidases. Molecules 26:.
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Franca, R., E. Veljkovic, S. Walter, C.A. Wagner, and F. Verrey. (2005). Heterodimeric amino acid transporter glycoprotein domains determining functional subunit association. Biochem. J. 388: 435-443.
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Jiang, Y. and M. Sun. (2024). SLC7A11: the Achilles heel of tumor? Front Immunol 15: 1438807.
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Keriel, A., E. Botella, S. Estrach, G. Bragagnolo, A.C. Vergunst, C.C. Feral, and D. O''Callaghan. (2015). Brucella Intracellular Life Relies on the Transmembrane Protein CD98 Heavy Chain. J Infect Dis 211: 1769-1778.
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Krautz-Peterson, G., S. Camargo, K. Huggel, F. Verrey, C.B. Shoemaker, and P.J. Skelly. (2007). Amino acid transport in schistosomes: Characterization of the permeaseheavy chain SPRM1hc. J. Biol. Chem. 282: 21767-21775.
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Liao, L., P. Yang, W. Zhang, S. Yu, H. Jing, and X. Zheng. (2024). CD98hc promotes drug resistance in extranodal natural killer/T cell lymphoma through tumor cell-derived small extracellular vesicles. Sci Signal 17: eadf9388.
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Malandro, M.S and M.S. Kilberg. (1996). Molecular biology of mammalian amino acid transporters. Annu. Rev. Biochem. 65: 305-336.
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Markovich, D., G. Stange, J. Bertran, M. Palacin, A. Werner, J. Biber, and H. Murer. (1993). Two mRNA transcripts (rBAT-1 and rBAT-2) are involved in system b0,+-related amino acid transport. J. Biol. Chem. 268: 1362-1367.
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Martin, K.R., J.A. Day, J.A. Hansen, D.B. D''Silva, H.L. Wong, A. Garnham, J.J. Sandow, B. Nijagal, N. Wilson, and I.P. Wicks. (2023). CD98 defines a metabolically flexible, proinflammatory subset of low-density neutrophils in systemic lupus erythematosus. Clin Transl Med 13: e1150.
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Mastroberardino, L., B. Spindler, R. Pfeiffer, P.J. Skelly, J. Loffing, C.B. Shoemaker, and F. Verrey. (1998). Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395: 288-291.
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Montero, J.C., E. Calvo-Jiménez, S. Del Carmen, M. Abad, A. Ocaña, and A. Pandiella. (2022). Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer. J Exp Clin Cancer Res 41: 106.
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Nguyen, N.N.T., Y.S. Lim, L.P. Nguyen, S.C. Tran, T.T.D. Luong, T.T.T. Nguyen, H.T. Pham, H.N. Mai, J.W. Choi, S.S. Han, and S.B. Hwang. (2018). Hepatitis C Virus Modulates Solute carrier family 3 member 2 for Viral Propagation. Sci Rep 8: 15486.
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Palacín, M. and Y. Kanai. (2004). The ancillary proteins of HATs: SLC3 family of amino acid transporters. Pflugers Arch 447: 490-494.
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Pandey, B., M. Aarthy, M. Sharma, S.K. Singh, and V. Kumar. (2020). Computational analysis identifies druggable mutations in human rBAT mediated Cystinuria. J Biomol Struct Dyn 1-10. [Epub: Ahead of Print]
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Puris, E., S. Auriola, S. Petralla, R. Hartman, M. Gynther, E.C.M. de Lange, and G. Fricker. (2022). Altered protein expression of membrane transporters in isolated cerebral microvessels and brain cortex of a rat Alzheimer''s disease model. Neurobiol Dis 169: 105741.
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Ren, Y., L. Fan, L. Wang, Y. Liu, J. Zhang, B. Wang, R. Chen, X. Chen, L. Zhuang, Y. Zhang, H. Sun, J. Li, W. Shi, and H. Jin. (2025). SSRP1/SLC3A2 Axis in Arginine Transport: A New Target for Overcoming Immune Evasion and Tumor Progression in Peripheral T-Cell Lymphoma. Adv Sci (Weinh) 12: e2415698.
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Rullo-Tubau, J., M. Martinez-Molledo, P. Bartoccioni, I. Puch-Giner, &.#.1.9.3.;. Arias, S. Saen-Oon, C. Stephan-Otto Attolini, R. Artuch, L. Díaz, V. Guallar, E. Errasti-Murugarren, M. Palacín, and O. Llorca. (2024). Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter. Nat Commun 15: 2986.
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Sato, H., A. Shiiya, M. Kimata, K. Maebara, M. Tamba, Y. Sakakura, N. Makino, F. Sugiyama, K. Yagami, T. Moriguchi, S. Takahashi, and S. Bannai. (2005). Redox imbalance in cystine/glutamate transporter-deficient mice. J. Biol. Chem. 280: 37423-37429.
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Torrents, D., R. Estévez, M. Pineda, E. Fernández, J. Lloberas, Y.-B. Shi, A. Zorzano, and M. Palacín. (1998). Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L: a candidate gene for lysinuric protein intolerance. J. Biol. Chem. 273: 32437-32445.
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Uemura, T., H.F. Yerushalmi, G. Tsaprailis, D.E. Stringer, K.E. Pastorian, L. Hawel, 3rd, C.V. Byus, and E.W. Gerner. (2008). Identification and characterization of a diamine exporter in colon epithelial cells. J. Biol. Chem. 283: 26428-26435.
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Xia, P. and A. Dubrovska. (2023). CD98 heavy chain as a prognostic biomarker and target for cancer treatment. Front Oncol 13: 1251100.
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Yan, Y., S. Vasudevan, H.T. Nguyen, and D. Merlin. (2008). Intestinal epithelial CD98: an oligomeric and multifunctional protein. Biochim. Biophys. Acta. 1780: 1087-1092.
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Zhang, J., F. Xiang, Y. Ding, W. Hu, H. Wang, X. Zhang, Z. Lei, T. Li, P. Wang, and X. Kang. (2024). Identification and validation of RNA-binding protein SLC3A2 regulates melanocyte ferroptosis in vitiligo by integrated analysis of single-cell and bulk RNA-sequencing. BMC Genomics 25: 236.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.A.9.1.1 | rBAT of 677 aas and 1 TMS. This protein is identical to the human ortholog. Computational analyses have identifies druggable mutations in human rBAT that mediate Cystinuria (Pandey et al. 2020). | Mammals | rBAT of Oryctolagus cuniculus |
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| 8.A.9.1.2 | Neutral and basic amino acid transport protein rBAT (NBAT) (B(0,+)-type amino acid transport protein) (D2h) | Animals | SLC3A1 of Homo sapiens |
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| 8.A.9.1.3 | Cell surface alpha-amylase (α-amylase), SusG of 692 aas and 1 N-terminal TMS. It forms a complex with SusCDEF, which are all outer membrane porins. SusC is 1.B.14.6.1; SusD is 1.B.38.1.10; SusE is 1.B.38.4.1, and SusF is 1.B.38.4.2. They form a complex for the hydrolysis of starch (amylose) and the uptake of maltooligosaccharides into the periplasm of the cell (Foley et al. 2018). | | SusG of Bacteroides thetaiotaomicron |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.A.9.2.1 | 4F2hc of 527 aas and 1 TMS. The 4F2/CDC98 cell surface receptor is involved in internalization of beta-defensin 3 (Colavita et al. 2015). | Mammals | 4F2hc of Rattus norvegicus |
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| 8.A.9.2.2 | The Slc3A2 (4F2; 4F2HC; 4F2hc; 4T2HC; CD98; CD98hc; MDU1; NACAE; SSRP1) accessory protein of 630 aas. It facilitates transport of amino acids and polyamines (putrescine/spermidine) (Uemura et al. 2008). 4F2hc stabilizes GLUT1 (2.A.1.1.28) and increase glucose transport activity (Ohno et al., 2011). It forms a heterodimer with glycoprotein CD98 (LAT1; SLC7A5), and contributes to tumorigenesis (Estrach et al. 2014). CD98hc also modulates integrin signaling, plays a role in cell-to-cell fusion, and is
essential for Brucella infection (Keriel et al. 2015). Hepatitis C virus (HCV) exploits SLC3A2 for viral propagation, and upregulation of SLC3A2 may contribute to HCV-mediated pathogenesis (Nguyen et al. 2018). ZEB1, a transcriptional repressor (P37275), promotes chemoresistance to cisplatin in ovarian cancer cells by suppressing SLC3A2 (Cui et al. 2018). SLC3A2/CD98hc and its light chain subunits constitute the heterodimeric transmembrane complexes that mediate amino acid transport and regulate MTOR and macroautophagy/autophagy (Digomann et al. 2019). It forms a tight complex with beta1 integrin (TC# 9.B.87.1.8) and TrpV4 (TC#
1.A.4.2.5) in focal adhesions where mechanochemical conversion takes
place. CD98hc knock down inhibits TRPV4-mediated calcium influx induced
by mechanical forces, but not by chemical activators, thus confirming
the mechanospecificity of this signaling response. Molecular analysis
revealed that forces applied to beta1 integrin must be transmitted from
its cytoplasmic C-terminus via the CD98hc cytoplasmic tail to the
ankyrin repeat domain of TRPV4 in order to produce ultra-rapid,
force-induced, channel activation within the focal adhesion (Potla et al. 2020). CD98hc is an antibody drug-conjugate target in triple negative breast cancer (Montero et al. 2022). N-glycosylation is crucial for trafficking and stability of SLC3A2 (Console et al. 2022). CD98 defines a metabolically flexible, proinflammatory subset of low-density neutrophils in systemic lupus erythematosus (Martin et al. 2023). RNA-binding protein SLC3A2 regulates melanocyte ferroptosis (Zhang et al. 2024). The non-natriuretic-dependent Xc- is composed of two protein subunits, SLC7A11 and
SLC3A2, with SLC7A11 serving as the primary functional component
responsible for cystine uptake and glutathione biosynthesis. SLC7A11 is
implicated in tumor development through its regulation of redox
homeostasis, amino acid metabolism, modulation of immune function, and
induction of programmed cell death. Jiang and Sun 2024 summarized the structure and biological
functions of SLC7A11, and the structure and mechanisms of transport of human Asc1/CD98hc amino acid transporterhave been reported, revealing determined at 3.4-3.8 Å resolution, revealing an inward-facing
semi-occluded conformation with Ser 246 and Tyr 333 being
essential for Asc1/CD98hc substrate selectivity and for the exchange and
facilitated diffusion modes of transport. (Rullo-Tubau et al. 2024). α-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding
α-2,3-linked sialosides are upregulated in melanoma, and targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins
involved in growth signaling, including the amino acid transporter, SLC3A2/CD98hc (Agrawal et al. 2024). The 4F2hc (Slc3a2) gene is expressed differentially in rat Alzheimer's Disease (Puris et al. 2022). The SSRP1/SLC3A2 protein plays a role in arginine transport and is a target for overcoming immune evasion and tumor progression in peripheral T-cell lymphoma (Ren et al. 2025). | Animals | SLC3A2 of Homo sapiens |
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| 8.A.9.2.3 | CD98hc, heavy chain of the heterodimeric CD998 (CG2791) amino acid transporter; involved in cell fusion, cell adhesion, TOR signalling, and amino acid transprot via LAT1 and LAT2 (see TC# 2.A.3.8.32) (Reynolds et al. 2009). CD98hc combines with one of six CD98lc proteins to regulate vascular smooth muscle cell proliferation in atherosclerosis (Baumer et al. 2017). CD98 heavy chain is a prognostic biomarker and target for cancer treatment (Xia and Dubrovska 2023). CD98hc promotes drug resistance in extranodal
natural killer/T cell lymphoma through tumor cell-derived small
extracellular vesicles (Liao et al. 2024). | Animals | CD98hc of Drosophila melanogaster (Fruit fly) |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.A.9.3.1 | SPRM1hc (Krautz-Peterson et al., 2007) | Worms | SPRM1hc of Schistosoma japonicum
(Q5DDT5) |
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