Article (Scientific journals)
A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma.
D'arrigo, Paolo; Russo, Michele; Rea, Anna et al.
2017In Oncotarget, 8 (40), p. 68291-68304
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Keywords :
FKBP51; PD-L1; SAFit; glioblastoma multiforme; ionizing radiation
Abstract :
[en] BACKGROUND: FKBP51 is a co-chaperone with isomerase activity, abundantly expressed in glioma. We previously identified a spliced isoform (FKBP51s) and highlighted a role for this protein in the upregulation of Programmed Death Ligand 1 (PD-L1) expression in melanoma. Because gliomas can express PD-L1 causing a defective host anti-tumoral immunity, we investigated whether FKBP51s was expressed in glioma and played a role in PD-L1 regulation in this tumour. METHODS: We used D54 and U251 glioblastoma cell lines that constitutively expressed PD-L1. FKBP51s was measured by immunoblot, flow cytometry and microscopy. In patient tumours, IHC and qPCR were used to measure protein and mRNA levels respectively. FKBP51s depletion was achieved by siRNAs, and its enzymatic function was inhibited using selective inhibitors (SAFit). We investigated protein maturation using N-glycosidase and cell fractionation approaches. RESULTS: FKBP51s was expressed at high levels in glioma cells. Glycosylated-PD-L1 was increased and reduced by FKBP51s overexpression or silencing, respectively. Naïve PD-L1 was found in the endoplasmic reticulum (ER) of glioma cells complexed with FKBP51s, whereas the glycosylated form was measured in the Golgi apparatus. SAFit reduced PD-L1 levels (constitutively expressed and ionizing radiation-induced). SAFit reduced cell death of PBMC co-cultured with glioma. CONCLUSIONS: Here we addressed the mechanism of post-translational regulation of PD-L1 protein in glioma. FKBP51s upregulated PD-L1 expression on the plasma membrane by catalysing the protein folding required for subsequent glycosylation. Inhibition of FKBP51s isomerase activity by SAFit decreased PD-L1 levels. These findings suggest that FKBP51s is a potential target of immunomodulatory strategies for glioblastoma treatment.
Disciplines :
Oncology
Author, co-author :
D'arrigo, Paolo ;  Université de Liège - ULiège > I3-Virology and Immunology
Russo, Michele
Rea, Anna
Tufano, Martina
Guadagno, Elia
Del Basso De Caro, Maria Laura
Pacelli, Roberto
Hausch, Felix
Staibano, Stefania
Ilardi, Gennaro
Parisi, Silvia
Romano, Maria Fiammetta
Romano, Simona
More authors (3 more) Less
Language :
English
Title :
A regulatory role for the co-chaperone FKBP51s in PD-L1 expression in glioma.
Publication date :
2017
Journal title :
Oncotarget
eISSN :
1949-2553
Publisher :
Impact Journals, United States - New York
Volume :
8
Issue :
40
Pages :
68291-68304
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 08 June 2020

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