Sequestration of NF-kappaB signaling complexes in lipid rafts contributes to repression of NF-kappaB in T lymphocytes under hyperthermia stress.
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 kappaB (NF-kappaB), which sensitizes cells to apoptosis mediated by inflammatory cytokine, tumor necrosis factor alpha. However, the molecular mechanism of hyperthermia-associated loss of T cells remains unclear. We show that hyperthermia causes rapid translocation of IkappaB kinase (IKK) and NF-kappaB 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 C theta (PKC theta) and Bcl10 to the microdomains, causing subsequent membrane translocation of the IKK and NF-kappaB signalosomes. Depletion of Carma1 and inhibition of PKC theta impair accumulation of NF-kappaB complexes in lipid rafts. Heat stress prohibits IkappaB kinase activity by sequestrating the IKK and NF-kappaB 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-kappaB and renders T cells resistant to tumor necrosis factor alpha-induced activation of IKK, thereby contributing to the apoptotic loss of T lymphocytes in sepsis-associated hyperthermia.
Yan
Guang
G
Department of Medicine, Microbiology and Immunology, and Penn State Cancer Institute, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Huang
Jiannan
J
Jarbadan
Nancy Ruth
NR
Jiang
Yixing
Y
Cheng
Hua
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D003902:Detergents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D051966:Phospholipase C gamma