Regulation of Translation Initiation by RNA Binding Proteins

Paul Babitzke; Carol S. Baker; Tony Romeo

doi:10.1146/annurev.micro.091208.073514

Viral and cellular mRNA-specific activators harness PABP and eIF4G to promote translation initiation downstream of cap binding

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610417114 ◽

2017 ◽

Vol 114 (24) ◽

pp. 6310-6315 ◽

Cited By ~ 15

Author(s):

Richard W. P. Smith ◽

Ross C. Anderson ◽

Osmany Larralde ◽

Joel W. S. Smith ◽

Barbara Gorgoni ◽

...

Keyword(s):

Translation Initiation ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Control Point ◽

Ribosomal Subunit ◽

Mrna Translation ◽

Initiation Factor ◽

Dependent Manner ◽

Translational Activation

Regulation of mRNA translation is a major control point for gene expression and is critical for life. Of central importance is the complex between cap-bound eukaryotic initiation factor 4E (eIF4E), eIF4G, and poly(A) tail-binding protein (PABP) that circularizes mRNAs, promoting translation and stability. This complex is often targeted to regulate overall translation rates, and also by mRNA-specific translational repressors. However, the mechanisms of mRNA-specific translational activation by RNA-binding proteins remain poorly understood. Here, we address this deficit, focusing on a herpes simplex virus-1 protein, ICP27. We reveal a direct interaction with PABP that is sufficient to promote PABP recruitment and necessary for ICP27-mediated activation. PABP binds several translation factors but is primarily considered to activate translation initiation as part of the PABP–eIF4G–eIF4E complex that stimulates the initial cap-binding step. Importantly, we find that ICP27-PABP forms a complex with, and requires the activity of, eIF4G. Surprisingly, ICP27–PABP–eIF4G complexes act independently of the effects of PABP-eIF4G on cap binding to promote small ribosomal subunit recruitment. Moreover, we find that a cellular mRNA-specific regulator, Deleted in Azoospermia-like (Dazl), also employs the PABP–eIF4G interaction in a similar manner. We propose a mechanism whereby diverse RNA-binding proteins directly recruit PABP, in a non–poly(A) tail-dependent manner, to stimulate the small subunit recruitment step. This strategy may be particularly relevant to biological conditions associated with hypoadenylated mRNAs (e.g., germ cells/neurons) and/or limiting cytoplasmic PABP (e.g., viral infection, cell stress). This mechanism adds significant insight into our knowledge of mRNA-specific translational activation and the function of the PABP–eIF4G complex in translation initiation.

Download Full-text

Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2021719118 ◽

2021 ◽

Vol 118 (6) ◽

pp. e2021719118 ◽

Cited By ~ 1

Author(s):

Aravinth Kumar Jayabalan ◽

Srivathsan Adivarahan ◽

Aakash Koppula ◽

Rachy Abraham ◽

Mona Batish ◽

...

Keyword(s):

Translation Initiation ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Early Stage ◽

Nonstructural Protein ◽

Granule Formation ◽

Adp Ribosylation ◽

Initiation Factors ◽

Translation Initiation Factors

While biomolecular condensates have emerged as an important biological phenomenon, mechanisms regulating their composition and the ways that viruses hijack these mechanisms remain unclear. The mosquito-borne alphaviruses cause a range of diseases from rashes and arthritis to encephalitis, and no licensed drugs are available for treatment or vaccines for prevention. The alphavirus virulence factor nonstructural protein 3 (nsP3) suppresses the formation of stress granules (SGs)—a class of cytoplasmic condensates enriched with translation initiation factors and formed during the early stage of infection. nsP3 has a conserved N-terminal macrodomain that hydrolyzes ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds the essential SG component G3BP1. Here, we show that macrodomain hydrolase activity reduces the ADP-ribosylation of G3BP1, disassembles virus-induced SGs, and suppresses SG formation. Expression of nsP3 results in the formation of a distinct class of condensates that lack translation initiation factors but contain G3BP1 and other SG-associated RNA-binding proteins. Expression of ADP-ribosylhydrolase–deficient nsP3 results in condensates that retain translation initiation factors as well as RNA-binding proteins, similar to SGs. Therefore, our data reveal that ADP-ribosylation controls the composition of biomolecular condensates, specifically the localization of translation initiation factors, during alphavirus infection.

Download Full-text