Eukaryotic Initiation Factor 4a3 Is a Selenium-Regulated RNA-Binding Protein that Selectively Inhibits Selenocysteine Incorporation

Abstract

Summary The synthesis of selenoproteins requires the translational recoding of the UGA stop codon as selenocysteine. During selenium deficiency, there is a hierarchy of selenoprotein expression, with certain selenoproteins synthesized at the expense of others. The mechanism by which the limiting selenocysteine incorporation machinery is preferentially utilized to maintain the expression of essential selenoproteins has not been elucidated. Here, we demonstrate that eukaryotic initiation factor 4a3 (eIF4a3) is involved in the translational control of a subset of selenoproteins. The interaction of eIF4a3 with the selenoprotein mRNA prevents the binding of SECIS binding Protein 2, which is required for selenocysteine insertion, thereby inhibiting the synthesis of the selenoprotein. Furthermore, the expression of eIF4a3 is regulated in response to selenium. Based on knockdown and overexpression studies, eIF4a3 is necessary and sufficient to mediate selective translational repression in cells. Our results support a model in which eIF4a3 links selenium status with differential selenoprotein expression.

Selenoproteins: Molecular Pathways and Physiological Roles

“…Instead of SBP2 and eEFSec, bacteria have a Sec-specific translation elongation factor (SelB in E. coli) that directly recognizes SECIS and is required for binding and delivery of SECIS elements to the ribosome (96). Since the discovery of SBP2, additional SECIS-binding proteins were identified and their roles in selenoprotein synthesis were characterized, including ribosomal protein L30 (53), eukaryotic initiation factor 4a3 (eIF4a3) (32), and nucleolin (254). While ribosomal protein L30 has been predicted to constitute a part of the basal Sec insertion machinery, nucleolin and eIF4a3 serve as regulatory proteins that modulate synthesis of selenoproteins and may contribute to the hierarchy of selenoprotein expression.…”

“…Recent studies have identified a eukaryotic translation initiation factor eIF4a3 as an important regulator of selenoprotein synthesis, which contributes to the preferential translation of essential selenoproteins during Se deficiency (32). eIF4a3 is a member of the DEAD box family of RNAdependent ATPases, which are involved in splicing of premRNA in the nucleus (217).…”

“…As part of its canonical function, eIF4a3 binds spliced mRNA during the formation of the exon junction complex and participates in NMD (52,112,279). In addition to performing its canonical function, eIF4a3 has been shown to serve as a negative regulator of Sec incorporation (32). eIF4a3 exhibits preferential binding to a subset of SECIS elements that are located in the 3=-UTR of stress-related selenoproteins, e.g., GPx1 and MsrB1, but has low affinity to the SECIS elements in mRNA from essential (housekeeping) selenoproteins, e.g., TR1 and GPx4.…”

Selective Up-regulation of Human Selenoproteins in Response to Oxidative Stress

“…These conditions have been shown previously to regulate selenoprotein expression in various cell lines after 24 h (18 -21, 23). In most cases, Ctrl medium is considered to be a seleniumlimiting condition (16,35). To evaluate the impact of H 2 O 2 treatment on cell proliferation at two selenium levels, we analyzed cell morphology by optical microscopy (Fig.…”

Secisbp2 is essential for embryonic development and enhances selenoprotein expression

“…Several other SECIS-binding proteins have since been identified. These include L30 (Rpl30), which is a component of the UGA recoding machinery (14), YB1 (48), NSEP1 (47), eIF4a3 (9), and nucleolin (33,56), which play roles in regulating UGA recoding. In addition, Secisbp2L binds to SECIS elements, but does not support Sec incorporation (19) [reviewed in Seeher et al (44)].…”