Surviving Stress by Going to Stress Granules

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Science's STKE  15 Mar 2005:
Vol. 2005, Issue 275, pp. tw99
DOI: 10.1126/stke.2752005tw99

Cells and even entire animals exposed to nonlethal stress, such as exposure to high temperature, tolerate subsequent stresses that would be lethal to a cell or animal not thus preconditioned. One mechanism for this effect of heat-stress preconditioning is inhibition of the inflammatory pathway mediated by nuclear factor κB (NF-κB) and the formation of stress granules, which results in the inhibition of mRNA translation. Kim et al. found that the adaptor protein TRAF2 [tumor necrosis factor receptor (TNFR)-associated factor 2] specifically associated with eIF4GI (eukaryotic translation initiation factor 4 γ1) in a yeast two-hybrid assay and in a glutathione S-transferase fusion protein pull-down assay, and these two proteins coimmunoprecipitated in unstressed cells. The interaction was specific for TRAF2 and not other isoforms of the TRAF family. eIF4GI is known to associate with stress granules, where it serves to sequester translation initiation factors, thereby blocking translation. The two proteins partially localized to stress granules in cells exposed to heat shock or sodium arsenite, based on either immunofluorescence analysis or appearance together in an insoluble cellular fraction. These stress granules persist for a time period that may account for the protective effects, but eventually the accumulation of eIF4GI and TRAF2 to them is reversible upon removal of the heat stress. Other components of the TNFR signaling complex were not localized to stress granules. Furthermore, treatment of cells undergoing heat stress with TNF-α did not promote the interaction of TRAF2 with TNFR as determined by coimmunoprecipitation. Activation of NF-κB by TNF-α [measured by electrophoresis mobility shift assay (EMSA)] was blocked during heat stress and for several hours after removal of the heat stress. Overexpression of eIF4GI inhibited TNF-α-stimulated activation of an NF-κB reporter, consistent with the idea that eIF4GI serves to sequester TRAF2, thus blocking signaling from the TNFR. Thus, the authors propose that, for a subset of nonlethal stresses, sequestration of a key component of the TNFR complex, TRAF2, blocks activation of the inflammatory mediator NF-κB stimulated by TNF-α. Further analysis is required to understand (i) how some stresses promote the formation of stress granules; (ii) how stresses that promote the formation of stress granules, but that do not promote sequestration of TRAF2 into these structures, provide a protective effect; and (iii) how stresses that do not promote stress granule formation mediate their protective effects.

W. J. Kim, S. H. Back, V. Kim, I. Ryu, S. K. Jang, Sequestration of TRAF2 into stress granules interrupts tumor necrosis factor signaling under stress conditions. Mol. Cell. Biol. 25, 2450-2462 (2005). [Abstract] [Full Text]

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