The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier
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The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier. / Kurtyka, Magdalena; Wessely, Frank; Bau, Sarah; Ifie, Eseoghene; He, Liqun; de Wit, Nienke M.; Pedersen, Alberte Bay Villekjær; Keller, Maximilian; Webber, Caleb; de Vries, Helga E.; Ansorge, Olaf; Betsholtz, Christer; De Bock, Marijke; Chaves, Catarina; Brodin, Birger; Nielsen, Morten S.; Neuhaus, Winfried; Bell, Robert D.; Letoha, Tamás; Meyer, Axel H.; Leparc, Germán; Lenter, Martin; Lesuisse, Dominique; Cader, Zameel M.; Buckley, Stephen T.; Loryan, Irena; Pietrzik, Claus U.
In: European Journal of Cell Biology, Vol. 103, No. 2, 151406, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier
AU - Kurtyka, Magdalena
AU - Wessely, Frank
AU - Bau, Sarah
AU - Ifie, Eseoghene
AU - He, Liqun
AU - de Wit, Nienke M.
AU - Pedersen, Alberte Bay Villekjær
AU - Keller, Maximilian
AU - Webber, Caleb
AU - de Vries, Helga E.
AU - Ansorge, Olaf
AU - Betsholtz, Christer
AU - De Bock, Marijke
AU - Chaves, Catarina
AU - Brodin, Birger
AU - Nielsen, Morten S.
AU - Neuhaus, Winfried
AU - Bell, Robert D.
AU - Letoha, Tamás
AU - Meyer, Axel H.
AU - Leparc, Germán
AU - Lenter, Martin
AU - Lesuisse, Dominique
AU - Cader, Zameel M.
AU - Buckley, Stephen T.
AU - Loryan, Irena
AU - Pietrzik, Claus U.
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024
Y1 - 2024
N2 - Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.
AB - Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.
KW - BBB
KW - brain drug delivery
KW - brain therapeutics
KW - CAT-1
KW - SLC7A1
KW - solute carriers
U2 - 10.1016/j.ejcb.2024.151406
DO - 10.1016/j.ejcb.2024.151406
M3 - Journal article
C2 - 38547677
AN - SCOPUS:85189017595
VL - 103
JO - Cytobiologie
JF - Cytobiologie
SN - 0724-5130
IS - 2
M1 - 151406
ER -
ID: 387935397