Integration of diverse inputs in the regulation of Caenorhabditis elegans DAF-16/FOXO

Abstract

In a remarkably conserved insulin signaling pathway that is well-known for its regulation of longevity in worms, flies, and mammals, the major C. elegans effector of this pathway, DAF-16/FOXO, also modulates many other physiological processes. This raises the question of how DAF-16/FOXO chooses the correct targets to achieve the appropriate response in a particular context. Here, we review current knowledge of tissue-specificity and interacting partners that modulate DAF-16/FOXO functional output.

Fig. 1. Insulin signaling regulation of DAF-16/FOXO

Activated DAF-2 initiates a phosphorylation cascade that ultimately phosphorylates DAF-16, thereby excluding it from the nucleus and inhibiting its activity. As noted in the text, it remains unclear whether DAF-16 interacts with both 14–3-3 proteins FTT-2 and PAR-5, so here we have labeled its interacting partner “14–3-3.”

Fig. 2. DAF-16 interacts with specific proteins under different stimuli

(a) Reduced insulin signaling relieves the phosphorylation of DAF-16, allowing it to enter the nucleus and interact with SMK-1 and BAR-1. (b) In response to oxidative stress, JNK-1 activates DAF-16 by phosphorylation. (Note that the phosphatase that may remove the inhibitory AKT/SGK phosphates to allow nuclear translocation is unknown, but the serine/threonine phosphatase PP2A dephosphorylates mammalian FOXO1 (Yan et al., 2008).) Activated DAF-16 accumulates in the nucleus, where it interacts with SIR-2.1/14–3-3, SMK-1, BAR-1, SKN-1, and HCF-1. (c). Heat shock causes JNK-1 to phosphorylate and activate DAF-16, which in turn, enters the nucleus and interacts with SIR-2.1/14–3-3 and HSF-1.

Fig. 2. DAF-16 interacts with specific proteins under different stimuli

(a) Reduced insulin signaling relieves the phosphorylation of DAF-16, allowing it to enter the nucleus and interact with SMK-1 and BAR-1. (b) In response to oxidative stress, JNK-1 activates DAF-16 by phosphorylation. (Note that the phosphatase that may remove the inhibitory AKT/SGK phosphates to allow nuclear translocation is unknown, but the serine/threonine phosphatase PP2A dephosphorylates mammalian FOXO1 (Yan et al., 2008).) Activated DAF-16 accumulates in the nucleus, where it interacts with SIR-2.1/14–3-3, SMK-1, BAR-1, SKN-1, and HCF-1. (c). Heat shock causes JNK-1 to phosphorylate and activate DAF-16, which in turn, enters the nucleus and interacts with SIR-2.1/14–3-3 and HSF-1.

Fig. 2. DAF-16 interacts with specific proteins under different stimuli

(a) Reduced insulin signaling relieves the phosphorylation of DAF-16, allowing it to enter the nucleus and interact with SMK-1 and BAR-1. (b) In response to oxidative stress, JNK-1 activates DAF-16 by phosphorylation. (Note that the phosphatase that may remove the inhibitory AKT/SGK phosphates to allow nuclear translocation is unknown, but the serine/threonine phosphatase PP2A dephosphorylates mammalian FOXO1 (Yan et al., 2008).) Activated DAF-16 accumulates in the nucleus, where it interacts with SIR-2.1/14–3-3, SMK-1, BAR-1, SKN-1, and HCF-1. (c). Heat shock causes JNK-1 to phosphorylate and activate DAF-16, which in turn, enters the nucleus and interacts with SIR-2.1/14–3-3 and HSF-1.