Translational Control Through the eIF4E Binding Proteins in the Brain

Mrna Translation ◽

Initiation Factor ◽

Initiation Step ◽

The Brain

Translation of messenger RNA (mRNA) into protein (protein synthesis) is a highly regulated process that controls gene expression. Various signaling pathways, including the mammalian target of rapamycin (mTOR), control mRNA translation at the initiation step. mTOR is part of a multi-subunit complex that regulates mRNA translation initiation by phosphorylating and inactivating the eukaryotic initiation factor 4E binding proteins (4E-BPs). 4E-BPs are a central mechanism in the control of cap-dependent translation in the brain. This chapter reviews the involvement of the 4E-BPs, particularly 4E-BP2, in brain development and synaptic transmission. Furthermore, it discusses the involvement of 4E-BP2 in autistic-like alterations, learning and memory, circadian rhythm regulation, and its roles in the pathophysiology and treatment of psychiatric (depressive disorders, schizophrenia) and neurodegenerative disorders (Parkinson’s).

4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.279.4.e715 ◽

2000 ◽

Vol 279 (4) ◽

pp. E715-E729 ◽

Cited By ~ 175

Author(s):

O. Jameel Shah ◽

Joshua C. Anthony ◽

Scot R. Kimball ◽

Leonard S. Jefferson

Keyword(s):

Translational Control ◽

Mrna Translation ◽

Cellular Protein ◽

Initiation Factor ◽

Translational Repressor ◽

Initiation Factors ◽

Initiation Phase ◽

Integration Sites ◽

A Site

Maintenance of cellular protein stores in skeletal muscle depends on a tightly regulated synthesis-degradation equilibrium that is conditionally modulated under an extensive range of physiological and pathophysiological circumstances. Recent studies have established the initiation phase of mRNA translation as a pivotal site of regulation for global rates of protein synthesis, as well as a site through which the synthesis of specific proteins is controlled. The protein synthetic pathway is exquisitely sensitive to the availability of hormones and nutrients and employs a comprehensive integrative strategy to interpret the information provided by hormonal and nutritional cues. The translational repressor, eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and the 70-kDa ribosomal protein S6 kinase (S6K1) have emerged as important components of this strategy, and together they coordinate the behavior of both eukaryotic initiation factors and the ribosome. This review discusses the role of 4E-BP1 and S6K1 in translational control and outlines the mechanisms through which hormones and nutrients effect changes in mRNA translation through the influence of these translational effectors.

Distinct Signaling Events Downstream of mTOR Cooperate To Mediate the Effects of Amino Acids and Insulin on Initiation Factor 4E-Binding Proteins

Molecular and Cellular Biology ◽

10.1128/mcb.25.7.2558-2572.2005 ◽

2005 ◽

Vol 25 (7) ◽

pp. 2558-2572 ◽

Cited By ~ 155

Author(s):

Xuemin Wang ◽

Anne Beugnet ◽

Mirei Murakami ◽

Shinya Yamanaka ◽

Christopher G. Proud

Keyword(s):

Amino Acids ◽

Mrna Translation ◽

Tissue Growth ◽

Mtor Signaling ◽

Initiation Factor ◽

Terminal Site ◽

New Strategies

ABSTRACT Signaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) undergoes phosphorylation at multiple sites. Here we show that amino acids regulate the N-terminal phosphorylation sites in 4E-BP1 through the RAIP motif in a rapamycin-insensitive manner. Several criteria indicate this reflects a rapamycin-insensitive output from mTOR. In contrast, the insulin-stimulated phosphorylation of the C-terminal site Ser64/65 is generally sensitive to rapamycin, as is phosphorylation of another well-characterized target for mTOR signaling, S6K1. Our data imply that it is unlikely that mTOR directly phosphorylates Thr69/70 in 4E-BP1. Although 4E-BP1 and S6K1 bind the mTOR partner, raptor, our data indicate that the outputs from mTOR to 4E-BP1 and S6K1 are distinct. In cells, efficient phosphorylation of 4E-BP1 requires it to be able to bind to eIF4E, whereas phosphorylation of 4E-BP1 by mTOR in vitro shows no such preference. These data have important implications for understanding signaling downstream of mTOR and the development of new strategies to impair mTOR signaling.

Contrasting mechanisms of regulating translation of specific Drosophila germline mRNAs at the level of 5′-cap structure binding

Biochemical Society Transactions ◽

10.1042/bst0331544 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1544-1546 ◽

Cited By ~ 2

Author(s):

P. Lasko ◽

P. Cho ◽

F. Poulin ◽

N. Sonenberg

Keyword(s):

Translational Control ◽

Binding Proteins ◽

Regulatory Mechanism ◽

Ribosomal Subunit ◽

Drosophila Embryo ◽

Initiation Factor ◽

Control Mechanisms ◽

Eukaryotic Initiation Factor ◽

Cognate Protein

Translational control is a key genetic regulatory mechanism underlying the initial establishment of the major spatial axes of the Drosophila embryo. Many translational control mechanisms target eIF4E (eukaryotic initiation factor 4E), an initiation factor that recognizes the 5′-cap structure of the mRNA. Cap recognition by eIF4E, in complex with eIF4G, is essential for recruitment of the mRNA to the small ribosomal subunit. One established mechanism for repressing translation involves eIF4E-binding proteins, which competitively inhibit the eIF4E–eIF4G interaction. Our group has uncovered a novel mechanism for repression in which an eIF4E cognate protein called d4EHP, which cannot bind eIF4G, binds to the 5′-cap structure of cad mRNA thus rendering it translationally inactive. These two related, but distinct, mechanisms are discussed and contrasted in this review.

Translational control of nociception via 4E-binding protein 1

eLife ◽

10.7554/elife.12002 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 18

Author(s):

Arkady Khoutorsky ◽

Robert P Bonin ◽

Robert E Sorge ◽

Christos G Gkogkas ◽

Sophie Anne Pawlowski ◽

...

Keyword(s):

Spinal Cord ◽

Translational Control ◽

Molecular Mechanisms ◽

Binding Protein ◽

Synaptic Activity ◽

Initiation Factor ◽

Thermal Pain ◽

Postsynaptic Protein ◽

Eukaryotic Initiation Factor 4E

Activation of the mechanistic/mammalian target of rapamycin (mTOR) kinase in models of acute and chronic pain is strongly implicated in mediating enhanced translation and hyperalgesia. However, the molecular mechanisms by which mTOR regulates nociception remain unclear. Here we show that deletion of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a major mTOR downstream effector, which represses eIF4E activity and cap-dependent translation, leads to mechanical, but not thermal pain hypersensitivity. Mice lacking 4E-BP1 exhibit enhanced spinal cord expression of neuroligin 1, a cell-adhesion postsynaptic protein regulating excitatory synapse function, and show increased excitatory synaptic input into spinal neurons, and a lowered threshold for induction of synaptic potentiation. Pharmacological inhibition of eIF4E or genetic reduction of neuroligin 1 levels normalizes the increased excitatory synaptic activity and reverses mechanical hypersensitivity. Thus, translational control by 4E-BP1 downstream of mTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception.

Translational control by RGS2

The Journal of Cell Biology ◽

10.1083/jcb.200811058 ◽

2009 ◽

Vol 186 (5) ◽

pp. 755-765 ◽

Cited By ~ 38

Author(s):

Chau H. Nguyen ◽

Hong Ming ◽

Peishen Zhao ◽

Lynne Hugendubler ◽

Robert Gros ◽

...

Keyword(s):

Protein Synthesis ◽

G Protein ◽

Translational Control ◽

Messenger Rna ◽

Mrna Translation ◽

Initiation Factor ◽

Rgs Proteins ◽

Rgs Domain ◽

Guanosine Triphosphatase ◽

Gtpase Cycle

The regulator of G protein signaling (RGS) proteins are a family of guanosine triphosphatase (GTPase)–accelerating proteins. We have discovered a novel function for RGS2 in the control of protein synthesis. RGS2 was found to bind to eIF2Bε (eukaryotic initiation factor 2B ε subunit) and inhibit the translation of messenger RNA (mRNA) into new protein. This effect was not observed for other RGS proteins tested. This novel function of RGS2 is distinct from its ability to regulate G protein–mediated signals and maps to a stretch of 37 amino acid residues within its conserved RGS domain. Moreover, RGS2 was capable of interfering with the eIF2–eIF2B GTPase cycle, which is a requisite step for the initiation of mRNA translation. Collectively, this study has identified a novel role for RGS2 in the control of protein synthesis that is independent of its established RGS domain function.

Multiple Mechanisms Control Phosphorylation of PHAS-I in Five (S/T)P Sites That Govern Translational Repression

Molecular and Cellular Biology ◽

10.1128/mcb.20.10.3558-3567.2000 ◽

2000 ◽

Vol 20 (10) ◽

pp. 3558-3567 ◽

Cited By ~ 137

Author(s):

Isabelle Mothe-Satney ◽

Daqing Yang ◽

Patrick Fadden ◽

Timothy A. J. Haystead ◽

John C. Lawrence

Keyword(s):

Mrna Translation ◽

Hek293 Cells ◽

Initiation Factor ◽

Translational Repression ◽

Phosphorylation Sites ◽

Translational Repressor ◽

Dependent Processes ◽

Constitutive Phosphorylation

ABSTRACT Control of the translational repressor, PHAS-I, was investigated by expressing proteins with Ser/Thr → Ala mutations in the five (S/T)P phosphorylation sites. Results of experiments with HEK293 cells reveal at least three levels of control. At one extreme is nonregulated phosphorylation, exemplified by constitutive phosphorylation of Ser82. At an intermediate level, amino acids and insulin stimulate the phosphorylation of Thr36, Thr45, and Thr69 via mTOR-dependent processes that function independently of other sites in PHAS-I. At the third level, the extent of phosphorylation of one site modulates the phosphorylation of another. This control is represented by Ser64 phosphorylation, which depends on the phosphorylation of all three TP sites. The five sites have different influences on the electrophoretic properties of PHAS-I and on the affinity of PHAS-I for eukaryotic initiation factor 4E (eIF4E). Phosphorylation of Thr45 or Ser64 results in the most dramatic decreases in eIF4E binding in vitro. However, each of the sites influences mRNA translation, either directly by modulating the binding affinity of PHAS-I and eIF4E or indirectly by affecting the phosphorylation of other sites.

The Interaction between Viral Messenger RNA and Eukaryotic Initiation Factor 2, a Protein Involved in Translational Control

Viral Messenger RNA ◽

10.1007/978-1-4613-2585-7_2 ◽

1985 ◽

pp. 21-48

Author(s):

Raymond Kaempfer

Keyword(s):

Translational Control ◽

Messenger Rna ◽

Initiation Factor ◽

Eukaryotic Initiation Factor ◽

Eukaryotic Initiation Factor 2 ◽

Initiation Factor 2

4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2025522118 ◽

2021 ◽

Vol 118 (15) ◽

pp. e2025522118

Author(s):

Vijendra Sharma ◽

Rapita Sood ◽

Danning Lou ◽

Tzu-Yu Hung ◽

Maxime Lévesque ◽

...

Keyword(s):

Animal Models ◽

Neuronal Cell ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Inhibitory Neurons ◽

Initiation Factor ◽

Seizure Threshold ◽

Parvalbumin Neurons

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.