Academic journal article Genetics

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2a Phosphorylation in Caenorhabditis Elegans

Academic journal article Genetics

Molecular Determinants of the Regulation of Development and Metabolism by Neuronal eIF2a Phosphorylation in Caenorhabditis Elegans

Article excerpt

PHOSPHORYLATION of the a-subunit of eukaryotic translation initiation factor 2 (eIF2a) is an evolutionarily conserved mechanism of translation control in eukaryotic cells that is pivotal for regulation of gene expression during stress (reviewed in Sonenberg and Hinnebusch 2009). In Saccharomyces cerevisiae, eIF2a phosphorylation by the eIF2a kinase GCN2 promotes cellular adaptation to nutrient deficiency by attenuating global protein synthesis and preferentially upregulating translation of transcripts that are associated with stress alleviation (Hinnebusch 2005). In mammals, four eIF2a kinases have been identified and are activated by endogenous and environmental cues that include amino acid starvation (GCN2), endoplasmic reticulum (ER) protein-folding imbalance (PERK), presence of foreign double-stranded RNA (PKR), and heme deprivation (HRI); hence constituting a homeostatic mechanism termed the integrated stress response (reviewed in Sonenberg and Hinnebusch 2009).

Phosphorylated eIF2a [eIF2(aP)] attenuates protein synthesis by sequestering the guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B), the activity of which is required for the GTP-binding eIF2 to initiate translation (reviewed in Sonenberg and Hinnebusch 2009). While the cellular consequences of eIF2a phosphorylation have been thoroughly delineated at the biochemical level (reviewed in Wek et al 2006; Sonenberg and Hinnebusch 2009), recent studies have also demonstrated tissue-specific roles of phosphorylation of eIF2a in animal physiology and disease. For instance, eIF2a phosphorylation and the eIF2a kinase GCN2 have been shown to regulate intestinal homeostasis and suppress gut inflammation (Cao et al. 2014; Ravindran et al. 2016). Recent studies have also highlighted complex physiological roles of eIF2a phosphorylation in the mammalian central nervous system. Specifically, essential amino acid deprivation induces phosphorylation of eIF2a via GCN2 in the mammalian anterior piriform cortex to promote aversion to an amino aciddeficient diet (Hao et al 2005; Maurin et al. 2005). Neuronal eIF2a phosphorylation also governs synaptic plasticity and learning by modulating expression of proteins involved in both long-term potentiation and depression at hippocampal synapses (Costa-Mattioli et al. 2007; Di Prisco et al. 2014). In addition, human genetic analyses have revealed that mutations in genes encoding translation initiation components regulating eIF2 activity, such as subunits of the exchange factor eIF2B and the g-subunit of eIF2, are associated with defects in myelination in the brain and mental disability, respectively (reviewed in Bugiani et al. 2010; Borck et al. 2012). Collectively, these findings indicate that, in addition to maintaining cellular homeostasis, neuronal eIF2a phosphorylation may exert cell-nonautonomous effects on organismal physiology and disease.

In Caenorhabditis elegans, environmental stressors, including those that induce translation attenuation such as nutrient limitation, trigger a state of developmental arrest termed dauer diapause, involving profound adaptations in metabolism, reproduction, and behavior (Cassada and Russell 1975). The genetic study of the dauer-developmental decision of C. elegans has served as an experimental paradigm for understanding how environmental cues influence organismal physiology through conserved neuroendocrine signaling pathways, including insulin and transforming growth factor-ß (TGFß) (reviewed in Hu 2007; Fielenbach and Antebi 2008). In a previous study, we characterized the mechanism by which the daf-28(sa191 ) mutation, previously isolated and molecularly characterized as a mutation in a gene encoding an insulin ligand (Malone and Thomas 1994; Li et al. 2003), causes constitutive dauer entry. The R37C substitution in the DAF-28 insulin peptide causes ER stress specifically in the ASI chemosensory neurons, activating the unfolded protein response (UPR) regulator PEK-1/PERK, which phosphorylates a conserved regulatory Ser49 in eIF2a in the ASI chemosensory neuron pair to promote entry into dauer diapause (Kulalert and Kim 2013). …

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