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Transcript
MODULATION OF NEURONAL PROTEIN SYNTHESIS BY “IMPACT”
Beatriz A. Castilho1, Martin Roffe1, Viviane S. Alves1, Catia M. Pereira1, Simone
Bittencourt2 and Luiz E. Mello2
1Dept. Microbiology/Immunology/Parasitology and 2Dept. Physiology, UNIFESP,
Rua Botucatu 862, São Paulo, SP, 04023-062, Brazil
Regulation of localized protein synthesis is intrinsic to processes of
synaptogenesis and synaptic plasticity. One of the central mechanisms
underlying regulation of translation in all eukaryotes is the phosphorylation of the
alpha subunit of eukaryotic Initiation Factor 2, which reduces general protein
synthesis but increases translation of specific mRNAs, such as ATF4/CREB-2 in
mammals. Phosphorylation of eIF2alpha and the consequent rise in ATF4
expression are the hallmarks of the pathway known as the Integrated Stress
Response (ISR), which ultimately results in the activation of a gene expression
network aimed at the recovery of the cells from the stress that initiated the ISR.
GCN2, one of the four eIF2 kinases in mammalian cells, is activated by
stresses such as amino acid starvation, proteasome inhibition and UV irradiation.
Recently, GCN2 has been implicated in the control of LTP and memory, in
feeding behavior and in amino acid and lipid metabolism in mice. We have
previously described the protein IMPACT as a GCN2 inhibitor, that competes
with GCN2 for the interaction with the activator GCN1. Overexpression of
IMPACT in cells inhibits GCN2 activation under different stress conditions. The
gene encoding IMPACT in mouse is imprinted, being expressed only from the
paternal allele. Imprinted genes are generally involved in developmental
processes. During development, we found that IMPACT expression is tightly
controlled. In the adult mouse, IMPACT is preferentially expressed in the brain.
Remarkably, areas in the brain where GCN2 activity has been found to be
relevant are devoid of IMPACT. On the other hand, IMPACT is highly expressed
in the majority of the neurons in the hypothalamus and brain stem, areas
involved in the maintenance of body homeostasis and the control of essential
body functions. These observations suggest that in these regions neuronal
protein synthesis can be kept constant even under physiological stresses that
would in other neuronal groups lead to GCN2 activation and protein synthesis
inhibition. At the cellular level, IMPACT is found in neuronal cell bodies, dendrites
and axons. IMPACT and GCN2 are present in synaptosomes, a sub-cellular
fraction enriched in pre- and post-synaptic elements. IMPACT is also abundant in
neuronal growth cones, areas of growth where protein synthesis must be kept at
a maximum, and co-localizes with F-actin. This suggests a possible interaction of
IMPACT with the cytoskeleton, which is supported by the observations that its
yeast ortholog co-purifies with actin. Thus, IMPACT emerges from these studies
as a major modulator of localized protein synthesis, specially relevant to neurons
in the adult brain.
Suppported by FAPESP