Abstract
Heat shock proteins are induced by activation of heat shock factor 1 (HSF1) in response to heat shock and protect against heat stress. However, the molecular mechanisms underlying the downstream signal of heat shock have not been fully elucidated. We found that similarly to canonical Hsps, Arc/Arg3.1 is also markedly induced by heat shock and by other cellular stress inducers, including diamide, sodium arsenite and H2O2 in various cells. We noted that heat stress–induced Arc/Arg3.1 protein is short lived, with a half-life of <30 min, and is readily degraded by the ubiquitin–proteasome system. Arc/Arg3.1 overexpression inhibited the up-regulation of heat shock–induced Hsp70 and Hsp27, suggesting that Arc/Arg3.1 is a negative regulator of heat shock response (HSR). Studying the effect of Arc/Arg3.1 on HSF1, a major transcription factor in HSR, we found that Arc/Arg3.1 binds to HSF1 and inhibits its binding to the heat shock element in gene promoters, resulting in reduced induction of Hsp27 and Hsp70 mRNAs, without affecting HSF1′s phosphorylation-dependent activation, or nuclear localization. Arc/Arg3.1 overexpression decreased cell survival in response to heat shock. We conclude that Arc/Arg3.1 is transiently expressed after heat shock and negatively regulates HSF1 in the feedback loop of HSR.
Highlights
45.3 kDa (396 amino acids) protein, rich in proline, glutamine, arginine and glutamic acid residues
In our heat shock response (HSR) system, we found that Arc/Arg3.1 inhibits the induction of Hsp[27] and Hsp[70] both in mRNA and protein levels by inhibiting the function of heat shock-induced heat shock factor 1 (HSF1) by reducing its binding to heat shock element (HSE)
Since Arc/Arg3.1 mRNA and protein were up- and down-regulated during recovery after heat shock, we investigated the kinetics of the changes in its expression during recovery after heat shock by Western analysis using anti-Arc antibody
Summary
45.3 kDa (396 amino acids) protein, rich in proline, glutamine, arginine and glutamic acid residues. Molecular function of Arc/Arg3.1 has been attributed to interactions with dynamin, a large GTPase essential for intracellular membrane trafficking including clathrin-mediated synaptic vesicle recycling, and endophilin, a protein playing a role in vesicle formation and function These interactions enhance the endocytosis of AMPA receptors which contributes to the synaptic transmission in LTD and homeostatic plasticity reduction[19]. In our HSR system, we found that Arc/Arg3.1 inhibits the induction of Hsp[27] and Hsp[70] both in mRNA and protein levels by inhibiting the function of heat shock-induced HSF1 by reducing its binding to HSE. These studies reveal a novel function of Arc/Arg3.1 in HSR of non-neuronal system
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