Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

Abstract

Within the last two decades, 4-hydroxynonenal has emerged as an important second messenger involved in the regulation of various cellular processes. Our recent studies suggest that HNE can induce apoptosis in various cells through the death receptor Fas (CD95)-mediated extrinsic pathway as well as through the p53-dependent intrinsic pathway. Interestingly, through its interaction with the nuclear protein Daxx, HNE can self-limit its apoptotic role by translocating Daxx to cytoplasm where it binds to Fas and inhibits Fas-mediated apoptosis. In this paper, after briefly describing recent studies on various biological activities of HNE, based on its interactions with Fas, Daxx, and p53, we speculate on possible mechanisms through which HNE may affect a multitude of cellular processes and draw a parallel between signaling roles of H(2)O(2) and HNE.

Fig. 1

HNE and signaling for apoptosis: HNE is diffusible and can interact with Fas on plasma membrane, cytoplasmic p53, and nuclear Daxx. HNE binds to Fas and activates the downstream kinases ASK1 and JNK leading to activation of caspase3 and apoptosis. In parallel, HNE interacts with cytoplasmic p53 leading to its activation via phosphorylation and translocation to the nucleus where it promotes transcription of proapoptotic/cell cycle arrest genes Bax/p21. HNE also interacts with the transcription repressor Daxx bound to HSF1, translocates Daxx from nucleus to cytoplasm where it binds to Fas, and inhibits activation of ASK1 to limit apoptosis. Release of free HSF1 leads to upregulated transcription of heat shock proteins.