Achilles is a circadian clock-controlled gene that regulates immune function in Drosophila

Abstract

The circadian clock is a transcriptional/translational feedback loop that drives the rhythmic expression of downstream mRNAs. Termed “clock-controlled genes,” these molecular outputs of the circadian clock orchestrate cellular, metabolic, and behavioral rhythms. As part of our on-going work to characterize key upstream regulators of circadian mRNA expression, we have identified a novel clock-controlled gene in Drosophila melanogaster, Achilles (Achl), which is rhythmic at the mRNA level in the brain and which represses expression of anti-microbial peptides in the immune system. Achilles knock-down in neurons dramatically elevates expression of crucial immune response genes, including IM1 (Immune induced molecule 1), Mtk (Metchnikowin), and Drs (Drosomysin). As a result, flies with knocked-down Achilles expression are resistant to bacterial challenges. Meanwhile, no significant change in core clock gene expression and locomotor activity is observed, suggesting that Achilles influences rhythmic mRNA outputs rather than directly regulating the core timekeeping mechanism. Notably, Achilles knock-down in the absence of immune challenge significantly diminishes the fly’s overall lifespan, indicating a behavioral or metabolic cost of constitutively activating this pathway. Together, our data demonstrate that (1) Achilles is a novel clock-controlled gene that (2) regulates the immune system, and (3) participates in signaling from neurons to immunological tissues.

Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer

“…The downstream genes regulated by clock genes are called clock-controlled genes (CCGs) (3). CCGs are involved in various physiological activities, including cell proliferation, apoptosis, cell cycling, metabolism, endocrine signaling and immunity (4)(5)(6)(7)(8). As a result, abnormal expression of clock genes can lead to a variety of diseases, including endocrine disorders, cardiovascular diseases and tumors (9)(10)(11)(12).…”

Acheron/Larp6 Is a Survival Protein That Protects Skeletal Muscle From Programmed Cell Death During Development

“…Transgenic flies expressing DMEF ( Drosophila Myocyte Enhancer Factor 2) driven red fluorescent protein (RFP) with or without Drosophila Acheron RNAi [CG17386/also known as Achilles in Drosophila ( Li et al, 2017 ) (or BBH1 (CG5059)] under the control of the Gal4 upstream activating sequence (UAS) were crossed to the DMEF-Gal4 driver line, which is expressed in all muscles. Flies were maintained at 25°C with a 12 h light/dark cycle, and both males and females were used in each experiment.…”

Aging and the clock: Perspective from flies to humans

“…Clock‐controlled genes also appear to play an important role in determining life span. In Drosophila , the recently characterized clock‐controlled gene Achilles regulates the immune system and provides a signaling link between neurons and immunological tissues (Li et al., ). Achilles is highly rhythmic in the brain with peak mRNA expression during the late dark period and trough expression during the late phase of the light cycle (Li et al., ).…”

“…In Drosophila , the recently characterized clock‐controlled gene Achilles regulates the immune system and provides a signaling link between neurons and immunological tissues (Li et al., ). Achilles is highly rhythmic in the brain with peak mRNA expression during the late dark period and trough expression during the late phase of the light cycle (Li et al., ). Even in the absence of an immune challenge, reduction of Achilles expression shortens life span (Li et al., ).…”

“…Achilles is highly rhythmic in the brain with peak mRNA expression during the late dark period and trough expression during the late phase of the light cycle (Li et al., ). Even in the absence of an immune challenge, reduction of Achilles expression shortens life span (Li et al., ). In mammalian models, numerous studies have demonstrated the interrelationship between circadian function and immune system responses (Curtis, Bellet, Sassone‐Corsi & O'Neill, ; Geiger, Fagundes & Siegel, ; Scheiermann, Kunisaki & Frenette, ).…”