liu.seSearch for publications in DiVA
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A protein disulfide isomerase/thioredoxin-1 complex is physically attached to exofacial membrane TNF-receptors: overexpression in chronic lymphocytic leukemia
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Department of Emergency Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden..
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. (Anders Rosén)ORCID iD: 0000-0001-5082-6423
2012 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, no 4, p. 363-375Article in journal (Refereed) Published
Abstract [en]

Aims: The 3D structures and functions of cysteine-rich receptors such as tumor necrosis factor receptors (TNFRs) are redox-modulated by dithiol–disulfide exchange. TNFR superfamily members participate in growth regulation in B-cell chronic lymphocytic leukemia (CLL), and tissue stromal cells interact with leukemia cells, profoundly affecting their viability via release of redox-active components, including cysteine, thioredoxin-1 (Trx1), and Trx reductase. Trx1 was previously shown to enhance release of TNF, which acts as an autocrine/paracrine growth factor in CLL. The nature of the mechanism is not known, however. Here, we investigated whether Trx1 and protein disulfide isomerase (PDI), a chaperone and Trx-family member, may interact with TNFRs. Results: We found direct physical association between PDI and TNFR1 or TNFR2 by coclustering and affinity isolation. PDI (57 kDa) formed covalent/reduction-sensitive 69-kDa complexes with Trx1 (12 kDa) in a majority of CLL cell samples, detected at low levels only in control B-cells. Functionally, the TNF/TNFR signaling via the nuclear factor kappa B-driven autocrine loop was disrupted in a dose-dependent fashion by PDI-inhibitors bacitracin, anti-PDI, or anti-Trx1 antibodies, resulting in reduced viability. PDI was significantly overexpressed in immunoglobulin heavy-chain variable (IGHV) unmutated versus mutated CLL (p=0.0102), and amplified TNF release was observed in the former group. Innovation: This study points out a previously unrecognized physical and functional association of TNFRs with the redox-active proteins PDI and Trx1. Conclusion: We describe here a new level of TNF regulation, in which membrane TNFRs are redox controlled at the exofacial surface by PDI/Trx1. These findings shed new light on the observed survival benefit in CLL B-cells exerted by TNFR-superfamily ligands and point at potential therapeutic strategies

Place, publisher, year, edition, pages
Mary Ann Liebert, 2012. Vol. 18, no 4, p. 363-375
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-79940DOI: 10.1089/ars.2012.4789ISI: 000312560700001OAI: oai:DiVA.org:liu-79940DiVA, id: diva2:544737
Available from: 2012-08-15 Created: 2012-08-15 Last updated: 2017-12-07

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full text

Authority records

Söderberg, AnitaRosén, Anders

Search in DiVA

By author/editor
Söderberg, AnitaRosén, Anders
By organisation
Cell BiologyFaculty of Health Sciences
In the same journal
Antioxidants and Redox Signaling
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 129 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf