Abstract
The ability to appropriately respond to proteotoxic stimuli is a major determinant of longevity and involves induction of various heat shock response (HSR) genes, which are essential to cope with cellular and organismal insults throughout lifespan. The activity of NAD+-dependent deacetylase Sir2, originally discovered in yeast, is known to be essential for effective HSR and longevity. Our previous work on HSR inDaphnia pulicaria indicated a drastic reduction of the HSR in older organisms. In this report we investigate the role of Sir2 in regulating HSR during the lifespan of D. pulicaria. We cloned Daphnia Sir2 open reading frame (ORF) to characterize the enzyme activity and confirmed that the overall function of Sir2 was conserved in Daphnia. The Sir2 mRNA levels increased while the enzyme activity declined with age and considering that Sir2 activity regulates HSR, this explains the previously observed age-dependent decline in HSR. Finally, we tested the effect of Sir2 knockdown throughout adult life by using our new RNA interference (RNAi) method by feeding. Sir2 knockdown severely reduced both the median lifespan as well as significantly increased mortality following heat shock. Our study provides the first characterization and functional study of Daphnia Sir2.
Highlights
The ability to respond to proteotoxic stress has proven to be a key regulator in the aging process in several model organisms [1, 2]
The longevity factor and deacetylase Sir2/Sirt1 plays a central role in coordinating cellular stress response including heat shock response (HSR) and affects an organism’s ability to respond effectively and appropriately to proteotoxic stress, especially in the context of aging [16, 46]
One of the deacetylation targets for human Sirt1 is HSF1, which is the transcription factor responsible for inducing the HSR [17], and only the deacetylated form of HSF1 is capable of binding to DNA
Summary
The ability to respond to proteotoxic stress has proven to be a key regulator in the aging process in several model organisms [1, 2]. One well-studied mechanism that regulates the aging process involves cellular responses to proteotoxic stress, referred to as proteostasis [2, 6]. The predominant cellular response to proteotoxic stimuli is the heat shock response (HSR), which has been studied extensively in numerous species [1]. The HSR involves the induction of molecular chaperones, termed heat shock proteins (Hsps) for relieving the molecular damage. Following a proteotoxic insult (heat shock, exposure to heavy metals, oxidative stress, or exposure to extreme pH), Hsp is induced transcriptionally by the transcription factor heat shock factor (HSF) [1, 9]. Upon heat shock or another proteotoxic event HSF undergoes trimerization and binds to specific sequences within the Hsp promoter to induce rapid and robust transcription to combat proteotoxic stress [1]
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