Sequestration of NF-κB signaling complexes in lipid rafts contributes to repression of NF-κB 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 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.