Sequestration of TRAF2 into Stress Granules Interrupts Tumor Necrosis Factor Signaling under Stress Conditions

Abstract

The cellular stress response (SR) is a phylogenetically conserved protection mechanism that involves inhibition of protein synthesis through recruitment of translation factors such as eIF4G into insoluble stress granules (SGs) and blockade of proinflammatory responses by interruption of the signaling pathway from tumor necrosis factor alpha (TNF-α) to nuclear factor-κB (NF-κB) activation. However, the link between these two physiological phenomena has not been clearly elucidated. Here we report that eIF4GI, which is a scaffold protein interacting with many translation factors, interacts with TRAF2, a signaling molecule that plays a key role in activation of NF-κB through TNF-α. These two proteins colocalize in SGs during cellular exposure to stress conditions. Moreover, TRAF2 is absent from TNFR1 complexes under stress conditions even after TNF-α treatment. This suggests that stressed cells lower their biological activities by sequestration of translation factors and TRAF2 into SGs through a protein-protein interaction.

ACKNOWLEDGMENTS

We thank David V. Goeddel of Tularik Inc. (San Francisco) for providing the FLAG-tagged TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 plasmid vectors. We also thank Sung Ho Ryu (Division of Molecular and Life Sciences, Pohang University of Science and Technology) and Jee Hee Youn (Department of Anatomy, College of Medicine, Hanyang University) for their valuable suggestions and critical review of the manuscript.

This work was supported in part by grants NRL (M10204000018-03J0000-01410) and MCBRG(M10106000056-03B4500-01010) from MOST, grants 02-PJ2-PG1-CH16-0002 and 405-VN02-0702-0008 from KHIDI, grant NCRC(R15-2004-033-01001-0) from KRF, and a grant from POSCO.