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Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules.

ABSTRACT: Stress granules (SGs) are large cytoplasmic ribonucleoprotein complexes that are assembled when cells are exposed to stress. SGs promote the survival of stressed cells by contributing to the reprogramming of protein expression as well as by blocking pro-apoptotic signaling cascades. These cytoprotective effects implicated SGs in the resistance of cancer cells to radiation and chemotherapy. We have found that sodium selenite, a selenium compound with chemotherapeutic potential, is a potent inducer of SG assembly. Selenite-induced SGs differ from canonical mammalian SGs in their morphology, composition and mechanism of assembly. Their assembly is induced primarily by eIF4E-binding protein1 (4EBP1)-mediated inhibition of translation initiation, which is reinforced by concurrent phosphorylation of eIF2α. Selenite-induced SGs lack several classical SG components, including proteins that contribute to pro-survival functions of canonical SGs. Our results reveal a new mechanism of mammalian SG assembly and provide insights into how selenite cytotoxicity may be exploited as an anti-neoplastic therapy.

SUBMITTER: Fujimura K

PROVIDER: S-EPMC3439927 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules.

Fujimura Ken K Sasaki Atsuo T AT Anderson Paul P

Nucleic acids research 20120620 16

Stress granules (SGs) are large cytoplasmic ribonucleoprotein complexes that are assembled when cells are exposed to stress. SGs promote the survival of stressed cells by contributing to the reprogramming of protein expression as well as by blocking pro-apoptotic signaling cascades. These cytoprotective effects implicated SGs in the resistance of cancer cells to radiation and chemotherapy. We have found that sodium selenite, a selenium compound with chemotherapeutic potential, is a potent induce ...[more]

PMID: 22718973

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Project description:In metazoans, germ cells play a fundamental role in ensuring the continuity of animal life. Germ cells contain germ granules, cytoplasmic non-membrane bound organelles also referred to as RNA-protein condensates. These germ granules house a variety of RNAs and proteins essential for germline identity, maintenance, and fertility. In C. elegans, P granules are a specific type of germ granule that localize to the nuclear periphery of developing germ cells and regulate mRNA expression. Proper P granule assembly is dependent on the PGL family of granule-forming proteins. PGL-1, the flagship P granule assembly protein and PGL member, contains two dimerization domains and a C-terminus region. Numerous proteins localize to P granules, most of which are RNA-binding or regulatory proteins. For example, IFE-1 is a eIF4E family member that binds the 5’ cap of mRNAs, directly interacts with PGL-1 in vivo and in vitro, and localizes to P granules. The precise molecular function of PGL and their associated proteins remains unclear; they may act solely as granule assembly proteins, serve as scaffolds to recruit other proteins, or directly regulate RNA. Here, genetics and imaging methods were used to molecularly dissect PGL-1 in vivo to probe how different protein regions are required for granule assembly, P granule binding partner recruitment, and germ cell development. We used CRISPR to (a) tag IFE-1 protein with an mScarlet fluorescent protein, (b) delete protein coding regions of pgl-1 to investigate IFE-1 binding and to understand how IFE-1 assembly into P granules is crucial for its role in germ cell development. Deletion of PGL-1 dimerization domains significantly disrupted P granule formation and IFE-1 recruitment. Removal of the C-terminus region led to abnormal P granule formation, which profoundly affected IFE-1 localization. These findings reveal that the previously uncharacterized C-terminal region plays a critical role in the integrity and functionality of P granules. We are performing immunoprecipitation assays to verify the direct binding of IFE-1 and PGL-1. Our study provides novel insights into the molecular mechanisms governing P granule protein interactions, highlighting their essential biological relevance and potential impact on understanding germ cell development.

Dataset Information

Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules.

Publications

Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules.

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