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

2021 ◽  
Vol 118 (6) ◽  
pp. e2021719118 ◽  
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.

scholarly journals Alphavirus nsP3 ADP-ribosylhydrolase Activity Disrupts Stress Granule Formation

2019 ◽  
Author(s):  
Aravinth Kumar Jayabalan ◽  
Diane E. Griffin ◽  
Anthony K. L. Leung
Keyword(s):  
Translation Initiation ◽  
Protein Modification ◽  
Nonstructural Protein ◽  
Host Protein ◽  
Granule Formation ◽  
Adp Ribosylation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Host Protein Synthesis ◽  
Lateral Sclerosis

ABSTRACTFormation of stress granules (SGs), cytoplasmic condensates of stalled translation initiation complexes, is regulated by post-translational protein modification. Alphaviruses interfere with SG formation in response to inhibition of host protein synthesis through the activities of nonstructural protein 3 (nsP3). nsP3 has a conserved N-terminal macrodomain that binds and can remove ADP-ribose from ADP-ribosylated proteins and a C-terminal hypervariable domain that binds essential SG component G3BP1. We showed that the hydrolase activity of chikungunya virus nsP3 macrodomain removed ADP-ribosylation of G3BP1 and suppressed SG formation. ADP-ribosylhydrolase-deficient nsP3 mutants allowed stress-induced cytoplasmic condensation of translation initiation factors. nsP3 also disassembled SG-like aggregates enriched with translation initiation factors that are induced by the expression of FUS mutant R495X linked to amyotrophic lateral sclerosis. Therefore, our data indicate that regulation of ADP-ribosylation controls the localization of translation initiation factors during virus infection and other pathological conditions.

scholarly journals The regulation of protein translation and its implications for cancer

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ping Song ◽  
Fan Yang ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Translation Initiation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Noncoding Rnas ◽  
Mrna Translation ◽  
Protein Translation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Precision Therapy ◽  
Novel Approaches

AbstractIn addition to the deregulation of gene transcriptions and post-translational protein modifications, the aberrant translation from mRNAs to proteins plays an important role in the pathogenesis of various cancers. Targeting mRNA translation are expected to become potential approaches for anticancer treatments. Protein translation is affected by many factors including translation initiation factors and RNA-binding proteins. Recently, modifications of mRNAs mainly N6-methyladenine (m6A) modification and noncoding RNAs, such as microRNAs and long noncoding RNAs are involved. In this review, we generally summarized the recent advances on the regulation of protein translation by the interplay between mRNA modifications and ncRNAs. By doing so, we hope this review could offer some hints for the development of novel approaches in precision therapy of human cancers.

Plant translation initiation factors: it is not easy to be green

2004 ◽  
Vol 32 (4) ◽  
pp. 589-591 ◽  
Author(s):  
K.S. Browning
Keyword(s):  
Translation Initiation ◽  
Binding Proteins ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Translational Machinery ◽  
Initiation Factors ◽  
Translation Initiation Factors

Plants have significant differences in some of the ‘parts’ of the translational machinery. There are two forms of eukaryotic initiation factor (eIF) 4F, eIF3 has two novel subunits, eIF4B is poorly conserved, and eIF2 kinases and eIF4E binding proteins (4E-BP) are yet to be discovered. These differences suggest that plants may regulate their translation in unique ways.

scholarly journals m6A-binding YTHDF proteins promote stress granule formation by modulating phase separation of stress granule proteins

2019 ◽  
Author(s):  
Ye Fu ◽  
Xiaowei Zhuang
Keyword(s):  
Phase Separation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Super Resolution ◽  
Stress Granule ◽  
Granule Formation ◽  
Intrinsically Disordered ◽  
Condensate Formation ◽  
Resolution Imaging

AbstractDiverse RNAs and RNA-binding proteins form phase-separated, membraneless granules in cells under stress conditions. However, the role of the prevalent mRNA methylation, m6A, and its binding proteins in stress granule (SG) assembly remain unclear. Here, we show that m6A-modified mRNAs are enriched in SGs, and that m6A-binding YTHDF proteins are critical for SG formation. Depletion of YTHDF1/3 inhibits SG formation and recruitment of m6A-modified mRNAs to SGs. Both the N-terminal intrinsically disordered region and the C-terminal m6A-binding YTH domain of YTHDF proteins are crucial for SG formation. Super-resolution imaging further reveals that YTHDF proteins are in a super-saturated state, forming clusters that reside in the periphery of and at the junctions between SG core clusters, and promote SG phase separation by reducing the activation energy barrier and critical size for condensate formation. Our results reveal a new function and mechanistic insights of the m6A-binding YTHDF proteins in regulating phase separation.

scholarly journals Polysomes of Trypanosoma brucei: Association with Initiation Factors and RNA-Binding Proteins

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135973 ◽  
Author(s):  
Cornelia Klein ◽  
Monica Terrao ◽  
Diana Inchaustegui Gil ◽  
Christine Clayton
Keyword(s):  
Trypanosoma Brucei ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Initiation Factors

scholarly journals Translational specialization in pluripotency by RBPMS poises future lineage-decisions

2021 ◽  
Author(s):  
Deniz Bartsch ◽  
Kaustubh Kalamkar ◽  
Gaurav Ahuja ◽  
Hisham Bazzi ◽  
Argyris Papantonis ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Translation Initiation ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Lineage Commitment ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Selective Translation

SUMMARYIn mammals, translation is uniquely regulated at the exit of pluripotency to rapidly reprogram the proteome to enable lineage commitment. Yet, the developmental mediators of translational control and their mode-of-action remain elusive. Using human embryonic stem cells, we identified RBPMS as a vital translation specialization factor that allows selective translation of developmental regulators. RBPMS-driven translational control balances the abundance of cell-fate regulators to enable accurate lineage decisions upon receiving differentiation cues. RBPMS loss, without affecting pluripotency, specifically and severely impedes mesoderm specification and subsequent cardiogenesis. Mechanistically, the direct binding of RBPMS to 3’UTR allows selective translation of transcripts encoding developmental regulators including integral components of central morphogen signaling networks specifying mesoderm. RBPMS-loss results in aberrant retention of key translation initiation factors on ribosomal complexes. Our data unveil how emerging lineage choices from pluripotency are controlled by translational specialization via ribosomal platforms acting as a regulatory nexus for developmental cell fate decisions.IN BRIEFFuture lineage choices from pluripotency are controlled by translational specialization. The RNA binding protein RBPMS is a vital translational specialization factor that unlocks the mesoderm commitment potential of pluripotent stem cells by enabling selective translation of cell-fate regulators instructing lineage decisions.HIGHLIGHTSLineage choices emerging from pluripotency are selectively controlled by translational specializationThe RNA-binding protein RBPMS is a translation specialization factor dedicated to mesoderm commitmentRBPMS-driven translational specialization enables accurate lineage commitment via balancing the availability of key morphogen signaling componentsRBPMS loss selectively impairs mesoderm commitment and subsequently impedes cardiogenesisRBPMS binds the 3’UTRs of target mRNAs to allow their selective translation; its depletion leads to aberrant retention of key translation initiation factors on ribosomal complexes

scholarly journals Positive mRNA Translational Control in Germ Cells by Initiation Factor Selectivity

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Andrew J. Friday ◽  
Brett D. Keiper
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Translation Initiation ◽  
Translational Control ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Positive Function ◽  
Initiation Factor ◽  
C Elegans ◽  
Initiation Factors

Ultimately, the production of new proteins in undetermined cells pushes them to new fates. Other proteins hold a stem cell in a mode of self-renewal. In germ cells, these decision-making proteins are produced largely from translational control of preexisting mRNAs. To date, all of the regulation has been attributed to RNA binding proteins (RBPs) that repress mRNAs in many models of germ cell development (Drosophila, mouse,C. elegans, andXenopus). In this review, we focus on the selective, positive function of translation initiation factors eIF4E and eIF4G, which recruit mRNAs to ribosomes upon derepression. Evidence now shows that the two events are not separate but rather are coordinated through composite complexes of repressors and germ cell isoforms of eIF4 factors. Strikingly, the initiation factor isoforms are themselves mRNA selective. The mRNP complexes of translation factors and RBPs are built on specific populations of mRNAs to prime them for subsequent translation initiation. Simple rearrangement of the partners causes a dormant mRNP to become synthetically active in germ cells when and where they are required to support gametogenesis.

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