dc.contributor.author |
Volkó, Julianna |
|
dc.contributor.author |
Kenesei, Ádám |
|
dc.contributor.author |
Zhang, Meili |
|
dc.contributor.author |
Várnai, Péter |
|
dc.contributor.author |
Mocsár, Gábor |
|
dc.contributor.author |
Petrus, Michael N |
|
dc.contributor.author |
Jambrovics, Károly |
|
dc.contributor.author |
Balajthy, Zoltán |
|
dc.contributor.author |
Müller, Gabriele |
|
dc.contributor.author |
Bodnár, Andrea |
|
dc.contributor.author |
Tóth, Katalin |
|
dc.contributor.author |
Waldmann, Thomas A |
|
dc.contributor.author |
Vámosi, György |
|
dc.date.accessioned |
2020-03-26T07:01:25Z |
|
dc.date.available |
2020-03-26T07:01:25Z |
|
dc.date.issued |
2019 |
|
dc.identifier |
85073312410 |
|
dc.identifier.citation |
journalVolume=116;journalIssueNumber=42;journalTitle=PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA;pagerange=21120-21130;journalAbbreviatedTitle=P NATL ACAD SCI USA; |
|
dc.identifier.uri |
http://repo.lib.semmelweis.hu//handle/123456789/8185 |
|
dc.identifier.uri |
doi:10.1073/pnas.1901382116 |
|
dc.description.abstract |
Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their heterotrimeric receptors share their β- and γc-chains, but have distinct α-chains. Anti-IL-2Rα (daclizumab) therapy targeting cell surface-expressed receptor subunits to inhibit T cell proliferation has only brought limited success in adult T cell leukemia/lymphoma (ATL) and in multiple sclerosis. We asked whether IL-2R subunits could already preassemble and signal efficiently in the endoplasmic reticulum (ER) and the Golgi. A combination of daclizumab and anti-IL-2 efficiently blocked IL-2-induced proliferation of IL-2-dependent wild-type (WT) ATL cells but not cells transfected with IL-2, suggesting that in IL-2-producing cells signaling may already take place before receptors reach the cell surface. In the Golgi fraction isolated from IL-2-producing ATL cells, we detected by Western blot phosphorylated Jak1, Jak3, and a phosphotyrosine signal attributed to the γc-chain, which occurred at much lower levels in the Golgi of WT ATL cells. We expressed EGFP- and mCherry-tagged receptor chains in HeLa cells to study their assembly along the secretory pathway. Confocal microscopy, Förster resonance energy transfer, and imaging fluorescence cross-correlation spectroscopy analysis revealed partial colocalization and molecular association of IL-2 (and IL-15) receptor chains in the ER/Golgi, which became more complete in the plasma membrane, further confirming our hypothesis. Our results define a paradigm of intracellular autocrine signaling and may explain resistance to antagonistic antibody therapies targeting receptors at the cell surface. |
|
dc.format.extent |
21120-21130 |
|
dc.relation.ispartof |
urn:issn:0027-8424 |
|
dc.title |
IL-2 receptors preassemble and signal in the ER/Golgi causing resistance to antiproliferative anti-IL-2Rα therapies |
|
dc.type |
Journal Article |
|
dc.date.updated |
2020-02-05T10:11:42Z |
|
dc.language.rfc3066 |
en |
|
dc.rights.holder |
NULL |
|
dc.identifier.mtmt |
30852788 |
|
dc.identifier.wos |
000490183000049 |
|
dc.identifier.pubmed |
31570576 |
|
dc.contributor.department |
SE/AOK/I/Élettani Intézet |
|
dc.contributor.institution |
Semmelweis Egyetem |
|