Abstract
In earlier studies, we showed that ATF4 down-regulation affects post-synaptic development and dendritic spine morphology in neurons through increased turnover of the Rho GTPase Cell Division Cycle 42 (Cdc42) protein. Here, we find that ATF4 down-regulation in both hippocampal and cortical neuron cultures reduces protein and message levels of RhoGDIα, a stabilizer of the Rho GTPases including Cdc42. This effect is rescued by an shATF4-resistant active form of ATF4, but not by a mutant that lacks transcriptional activity. This is, at least in part, due to the fact that Arhgdia, the gene encoding RhoGDIα, is a direct transcriptional target of ATF4 as is shown in ChIP assays. This pathway is not restricted to neurons. This is seen in an impairment of cell migration on ATF4 reduction in non-neuronal cells. In conclusion, we have identified a new cellular pathway in which ATF4 regulates the expression of RhoGDIα that in turn affects Rho GTPase protein levels, and thereby, controls cellular functions as diverse as memory and cell motility.
Highlights
Activating Transcription Factor 4 (ATF4) is a ubiquitously expressed member of the ATF/CREB transcription factor family of basic leucine zipper domain proteins that is involved in a wide range of activities and biological functions[1]
Because Rho GTPase proteins are degraded by the proteasome[25], we first assessed whether ATF4 knockdown affects the expression of E3 ubiquitin ligases
There is no identified E3 ubiquitin ligase specific for Cdc[42], but Smurf[1] has been shown to mediate degradation of RhoA26, the levels of which decrease with ATF4 knockdown[15]
Summary
Activating Transcription Factor 4 (ATF4) is a ubiquitously expressed member of the ATF/CREB transcription factor family of basic leucine zipper domain proteins that is involved in a wide range of activities and biological functions[1]. Our studies on the mechanisms underlying ATF4′s effects on dendritic spines and excitatory synapses revealed that depletion of basal ATF4 in cortical and hippocampal neurons elevates turnover of the Rho GTPase Cell Division Cycle 42 (Cdc42) protein without affecting its synthesis, thereby lowering total protein expression by 40–60%15. Knockdown of ATF4 leads to a decreased expression of total and active forms of the Rho GTPase family member RhoA, this effect does not appear to contribute to loss of spines or excitatory synapses[15]. The effect of ATF4 knockdown on Cdc[42] expression is rescued by over-expression of wild-type ATF4, but is not rescued by comparable over-expression of a form of ATF4 mutated to eliminate its transcriptional activity[15] This could be explained by ATF4-mediated transcriptional regulation of another gene(s) that in turn affects Cdc[42] stability and turnover
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