Comparative proteomics of exosomes secreted by tumoral Jurkat T cells and normal human T cell blasts unravels a potential tumorigenic role for valosin-containing protein
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Alberto Bosque1,4,*, Lisa Dietz2,*, Ana Gallego-Lleyda1,*, Manuel Sanclemente1, María Iturralde1, Javier Naval1, María Angeles Alava1, Luis Martínez-Lostao1,3,5,#, Hermann-Josef Thierse2,#, Alberto Anel1,#
1Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Instituto de Investigación Sanitaria de Aragón (IIS-Aragón), Zaragoza, Spain
2Research Group for Immunology & Proteomics, Department of Dermatology, University Medical Center Mannheim, Ruprechts-Karls-University, Heidelberg, Germany
3Instituto de Nanociencia de Aragón (INA), Zaragoza, Spain
4Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
5Servicio de Inmunología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
*These authors contributed equally to this work
#Shared senior authorship
Alberto Anel, email: [email protected]
Hermann-Josef Thierse, email: [email protected]
Keywords: leukemia, T cells, exosomes, apoptosis, proteomics
Received: December 21, 2015 Accepted: March 28, 2016 Published: April 11, 2016
We have previously characterized that FasL and Apo2L/TRAIL are stored in their bioactive form inside human T cell blasts in intraluminal vesicles present in multivesicular bodies. These vesicles are rapidly released to the supernatant in the form of exosomes upon re-activation of T cells. In this study we have compared for the first time proteomics of exosomes produced by normal human T cell blasts with those produced by tumoral Jurkat cells, with the objective of identify proteins associated with tumoral exosomes that could have a previously unrecognized role in malignancy. We have identified 359 and 418 proteins in exosomes from T cell blasts and Jurkat cells, respectively. Interestingly, only 145 (around a 40%) are common. The major proteins in both cases are actin and tubulin isoforms and the common interaction nodes correspond to these cytoskeleton and related proteins, as well as to ribosomal and mRNA granule proteins. We detected 14 membrane proteins that were especially enriched in exosomes from Jurkat cells as compared with T cell blasts. The most abundant of these proteins was valosin-containing protein (VCP), a membrane ATPase involved in ER homeostasis and ubiquitination. In this work, we also show that leukemic cells are more sensitive to cell death induced by the VCP inhibitor DBeQ than normal T cells. Furthermore, VCP inhibition prevents functional exosome secretion only in Jurkat cells, but not in T cell blasts. These results suggest VCP targeting as a new selective pathway to exploit in cancer treatment to prevent tumoral exosome secretion.
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