Date Published: January 15, 2019
Publisher: Impact Journals
Author(s): Zachary Kopp, Yongkyu Park.
Downregulation of Rpd3 (histone deacetylase) or Loco (regulator of G-protein signaling protein) extends Drosophila lifespan with higher stress resistance. We found rpd3-downregulated long-lived flies genetically interact with loco-upregulated short-lived flies in stress resistance and lifespan. Gene expression profiles between those flies revealed that they regulate common target genes in metabolic enzymes and signaling pathways, showing an opposite expression pattern in their contrasting lifespans. Functional analyses of more significantly changed genes indicated that the activities of catabolic enzymes and uptake/storage proteins are reduced in long-lived flies with Rpd3 downregulation. This reduced catabolism exhibited from a young age is considered to be necessary for the resultant longer lifespan of the Rpd3- and Loco-downregulated old flies, which mimics the dietary restriction (DR) effect that extends lifespan in the several species. Inversely, those catabolic activities that break down carbohydrates, lipids, and peptides were high in the short lifespan of Loco-upregulated flies. Long noncoding gene, dntRL (CR45923), was also found as a putative target modulated by Rpd3 and Loco for the longevity. Interestingly, this dntRL could affect stress resistance and lifespan, suggesting that the dntRL lncRNA may be involved in the metabolic mechanism of Rpd3 and Loco signaling.
Rpd3, a Drosophila histone deacetylase (HDAC), modulates chromatin structures and affects signaling pathways by interacting with several chromatin remodeling complexes [1-3]. The Rpd3 protein is known to mediate epigenetic effects like long-term memory and lifespan. The adult brain-specific changes of Rpd3 expression results in impaired long-term courtship memory . However, systemic downregulation of Rpd3 extends lifespan [5,6], which is also observed in yeast with reduced Rpd3 expression . Recently, it has been reported that Rpd3 interacts partially with the insulin signaling longevity pathway . As several long-lived mutant flies display increased resistance to numerous stressors including oxidation, starvation, and heat compared to wild-type flies [9-12], Rpd3 downregulation also enhances stress resistance with extended lifespan . Inhibition of mammalian HDACs is shown to be a proven anticancer therapeutic and potential treatment of many other diseases including HIV infection, Alzheimer’s disease, and cardiac remodeling [13,14]. Consistently, it was recently reported that decreased Rpd3 expression in Drosophila heart tissue enhances cardiac function (decreased heart failure and accelerated heart recovery) and resistance against stressors .
Rpd3 or Loco downregulation extends lifespan with higher stress resistance [5,6,19]. Here, we found that the nuclear protein Rpd3 genetically interacts with the cytoplasmic membrane-associated protein Loco in the longevity mechanism (Figure 1A-D). Given that the changes in Rpd3 and Loco did not affect the expression of each other (Figure 2C), they may interact post-translationally through a signaling pathway. As a regulator of G-protein signaling protein, Loco increases adenylate cyclase (AC) activity by inactivating the inhibitory Gαi•GTP protein [17,18,33], and the mammalian homologue, RGS14, interacts with activated H-Ras and Raf-1 kinases, which subsequently inhibit ERK phosphorylation [37-39]. Consistently, we previously showed that downregulation of Loco significantly diminishes cAMP amounts  and increases p-ERK levels with higher resistance to the oxidative stress . In mammals, p-ERK is shown to interact with PP1 (protein phosphatase 1) that dephosphorylates p-HDAC1 [40-42]. Considering mammalian HDAC1 phosphorylation promotes complex formation and enhances the enzyme activity of HDAC1 [42-44], one possibility is that Loco downregulation may decrease Rpd3 activity through the reduction of phospho-Rpd3 levels, subsequently resulting in the longer lifespan (Figure 1).