Autophagy activation by NFκB is essential for cell survival after heat shock

Abstract

The heat shock response is a widely described defense mechanism during which the preferential expression of heat shock proteins (Hsps) helps the cell to recover from thermal damages such as protein denaturation/aggregation. We have previously reported that NFκB transcription factor is activated during the recovery period after heat shock. In this study, we analyze the consequences of NFκB activation during heat shock recovery, by comparing the heat shock response of NFκB competent and incompetent (p65/RelA-depleted) cells. We demonstrate for the first time that NFκB plays a major and crucial role during the heat shock response by activating autophagy, which increases survival of heat-treated cells. Indeed, we observed that autophagy is not activated during heat shock recovery and cell death is strongly increased in NFκB incompetent cells. Moreover, if autophagy is artificially induced in these cells, the cytotoxicity of heat shock is turned back to normal. We show that despite a post-heat shock increase of Beclin 1 level in NFκB competent cells, neither Beclin 1/class III PI3K complex, Bcl2/Bcl-XL nor mTOR kinase are NFκB targets whose modulation of expression could be responsible for NFκB activation of autophagy during heat shock recovery. In contrast, we demonstrate that aberrantly folded/aggregated proteins are prime events in the signaling pathway leading to NFκB mediated autophagy after heat shock. Hence, our findings demonstrate that NFκB-induced autophagy during heat shock recovery is an additional cell response to HS-induced protein denaturation/aggregation; this mechanism increases cell survival, probably through clearance of irreversibly damaged proteins. ©2009 Landes Bioscience.