Sequestration of NF-κB Signaling Complexes in Lipid Rafts Contributes to Repression of NF-κB in T Lymphocytes under Hyperthermia Stress*
- ‡Department of Medicine, ¶Microbiology and Immunology, and §Penn State Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania 17033
- 2 To whom correspondence should be addressed: Penn State Cancer Institute, Oncology Room 6818, 500 University Dr., Hershey, PA17033. Tel.: 717-531-3863; Fax: 717-531-5076; E-mail: hcheng{at}hmc.psu.edu.
Abstract
Sepsis causes extensive apoptosis of lymphocytes, a pathological condition that is frequently associated with hyperthermia. Heat stress has been implicated to repress the activation of an inflammatory mediator, nuclear factor of κB (NF-κB), which sensitizes cells to apoptosis mediated by inflammatory cytokine, tumor necrosis factor α. However, the molecular mechanism of hyperthermia-associated loss of T cells remains unclear. We show that hyperthermia causes rapid translocation of IκB kinase (IKK) and NF-κB complexes into the plasma membrane-associated lipid rafts in T cells. Heat stress induces aggregation of Carma1 in lipid rafts, which in turn recruits protein kinase Cθ (PKCθ) and Bcl10 to the microdomains, causing subsequent membrane translocation of the IKK and NF-κB signalosomes. Depletion of Carma1 and inhibition of PKCθ impair accumulation of NF-κB complexes in lipid rafts. Heat stress prohibits IκB kinase activity by sequestrating the IKK and NF-κB complexes in lipid rafts and by segregating the chaperone protein Hsp90, an essential cofactor for IKK, from the IKK complex. This process ultimately results in functional deficiency of NF-κB and renders T cells resistant to tumor necrosis factor α-induced activation of IKK, thereby contributing to the apoptotic loss of T lymphocytes in sepsis-associated hyperthermia.
Footnotes
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↵3 The abbreviations used are: TNF, tumor necrosis factor α; IL-1, interleukine-1; JNK, c-Jun N-terminal kinase; P/I, phorbol 12-myristate 13-acetate/ionomycin; IKK, IκB kinase; TCR, T cell receptor; PKC, protein kinase C; MβCD, methyl-β-cyclodextrin; GST, glutathione S-transferase; GFP, green fluorescent protein; HEK cells, human embryonic kidney cells; PBS, phosphate-buffered saline; HS, heat shock; DR, detergent-resistant; ERK, extracellular signal-regulated kinase; PLC, phospholipase C; LAT, linker for activation of T cells.
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↵* This work was supported by a fund from Penn State Cancer Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 These authors contributed equally to this work.
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- Received September 24, 2007.
- Revision received February 19, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
