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Stress Granule Formation, Disassembly, and Composition Are Regulated by Alphavirus ADP-Ribosylhydrolase Activity

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Stress Granule Formation, Disassembly, and Composition Are Regulated by Alphavirus ADP-Ribosylhydrolase Activity Stress granule formation, disassembly, and composition are regulated by alphavirus ADP-ribosylhydrolase activity Aravinth Kumar Jayabalana, Srivathsan Adivarahanb, Aakash Koppulac, Rachy Abrahamd, Mona Batishc,e, Daniel Zenklusenb, Diane E. Griffind, and Anthony K. L. Leunga,f,g,1 aDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; bDépartment de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3T 1J4, Canada; cDepartment of Biological Sciences, University of Delaware, Newark, DE 19716; dW. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; eDepartment of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716; fDepartment of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205; and gDepartment of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205 Edited by Thomas Shenk, Princeton University, Princeton, NJ, and approved December 31, 2020 (received for review October 22, 2020) While biomolecular condensates have emerged as an important later infection stages, many viruses instead suppress SG forma- biological phenomenon, mechanisms regulating their composition tion or disassemble SGs altogether. The mechanisms underlying and the ways that viruses hijack these mechanisms remain unclear. this switch, and its physiological function, remain unclear. The mosquito-borne alphaviruses cause a range of diseases from SG formation and disassembly are regulated by posttransla- rashes and arthritis to encephalitis, and no licensed drugs are tional modifications of proteins, including those that conjugate available for treatment or vaccines for prevention. The alphavirus simple chemical groups, attach polypeptides, and add nucleotides virulence factor nonstructural protein 3 (nsP3) suppresses the for- as in the case of ADP-ribosylation (15–21). ADP-ribosylation re- mation of stress granules (SGs)—a class of cytoplasmic condensates fers to the addition of one or more ADP-ribose units onto proteins enriched with translation initiation factors and formed during the (22–24). In humans, ADP-ribosylation is accomplished primarily early stage of infection. nsP3 has a conserved N-terminal macrodo- by a family of 17 ADP-ribosyltransferases, commonly known as main that hydrolyzes ADP-ribose from ADP-ribosylated proteins and poly(ADP-ribose) polymerases (PARPs). SG components are spe- MICROBIOLOGY a C-terminal hypervariable domain that binds the essential SG com- cifically ADP-ribosylated, and ADP-ribose polymers [i.e., poly(ADP- ponent G3BP1. Here, we show that macrodomain hydrolase activity ribose) or PAR], five PARPs and two isoforms of the degradative reduces the ADP-ribosylation of G3BP1, disassembles virus-induced enzyme PAR glycohydrolase (PARG) have been localized to these SGs, and suppresses SG formation. Expression of nsP3 results in the condensates (17, 25–27). Overexpression of these PARPs and formation of a distinct class of condensates that lack translation PARG isoforms induces and suppresses SG formation, respec- initiation factors but contain G3BP1 and other SG-associated RNA- tively, while PARG knockdown delays SG disassembly (17, 26). binding proteins. Expression of ADP-ribosylhydrolase–deficient nsP3 The noncovalent interaction between PAR and proteins facili- results in condensates that retain translation initiation factors as tates SG targeting (25–27). For example, PAR-mediated targeting well as RNA-binding proteins, similar to SGs. Therefore, our data regulates TDP-43 localization to SGs and prevents the formation reveal that ADP-ribosylation controls the composition of biomolec- of pathological aggregates in amyotrophic lateral sclerosis (26, 27). ular condensates, specifically the localization of translation initiation factors, during alphavirus infection. Significance ADP-ribosylation | stress granules | biomolecular condensates | Alphaviruses are mosquito-borne RNA viruses that cause rash, alphavirus | macrodomain arthritis, and neurologic disease. Despite a continued risk of outbreaks, there are no licensed interventions for any alpha- iomolecular condensates are prevalent in cells and critical virus. For progress in control, an understanding of the molecular Bfor a range of cellular functions, including RNA metabolism, targets that affect virus replication and virulence is essential. embryonic cell fate specification, and neuronal activity (1–3). This paper characterizes a conserved macrodomain in the viru- While condensates often dynamically exchange components with lence factor nonstructural protein 3 (nsP3). We discovered that the surrounding milieu, the overall composition of these cellular the macrodomain ADP-ribosylhydrolase activity is critical for structures remains distinct (4). How cells control the specific controlling the composition of cellular condensates, specifically composition of these condensates remains unclear. Stress granules through regulating the localization of translation factors, during (SGs), one of the best characterized biomolecular condensates, are viral infection. Given that this macrodomain is conserved across RNA–protein assemblies formed in response to a variety of envi- alphaviruses and coronaviruses and that the associated enzy- ronmental cues (1). While SG composition can vary with the type matic activity is critical for virulence, our work may open ave- of stress cue (5), certain common components, such as Ras GTP- nues for developing a class of antiviral therapeutics. activating protein-binding proteins G3BP1/2, are essential for for- Author contributions: A.K.J., M.B., D.Z., D.E.G., and A.K.L.L. designed research; A.K.J., S.A., mation of SGs (6, 7). Dysregulation of SG formation and disas- A.K., and R.A. performed research; A.K.J. and R.A. contributed new reagents/analytic sembly is implicated in the pathogenesis of diseases, including viral tools; A.K.J., S.A., A.K., D.E.G., and A.K.L.L. analyzed data; and A.K.J. and A.K.L.L. wrote infection, cancer, and neurodegeneration (2, 8–10). the paper. SG formation and disassembly are tightly regulated during The authors declare no competing interest. viral infection, often reflecting cellular translation status (11–14). This article is a PNAS Direct Submission. In the early phase of many viral infections, the presence of Published under the PNAS license. double-stranded viral RNAs (vRNAs) activate protein kinase R 1To whom correspondence may be addressed. Email: [email protected]. α (PKR), resulting in eIF2 phosphorylation, messenger RNA This article contains supporting information online at https://www.pnas.org/lookup/suppl/ (mRNA) translation inhibition, and formation of SGs enriched doi:10.1073/pnas.2021719118/-/DCSupplemental. with translation initiation factors such as eIF3b. However, in Published February 5, 2021. PNAS 2021 Vol. 118 No. 6 e2021719118 https://doi.org/10.1073/pnas.2021719118 | 1of11 Downloaded by guest on September 29, 2021 ADViral infection B mRNA binding Translation CHIKV (hpi) proteins factors 0246810 nsP3 nsP3 nsP3 p-eIF2α TIA1 eIF3b TIA1 eIF2α eIF3b β-actin Merge Merge Image Fig. 1. Two distinct classes of biomolecular con- acquisition nsP3 nsP3 nsP3 densates form during alphavirus infection. (A) U2OS SGs SGs condensates TIAR eIF3i cells stably expressing GFP-eIF3g were infected with eIF3i appear (I) disappear (II) appear (III) TIAR WT CHIKVmCherry at MOI of 10, subjected to live cell Merge Merge imaging with the time-lapse interval of 12 min over nsP3 nsP3 t = 120 min t = 360 min t = 540 min 14 h. Images shown are the snapshots of different HuR RACK1 infection stages. (B) U2OS cells were either mock- HuR Merge RACK1 Merge infected or infected with CHIKV. Twelve hours post- infection, cells were lysed and blotted against nsP3 nsP3 indicated antibodies. (C) Violin plot shows the dis- G3BP1 RPS6 tribution of time points (minutes) representing SG GFP-eIF3g / mCherry-CHIKV RPS6 G3BP1 Merge Merge appearance, disappearance, and nsP3 condensate appearance. Ninety-seven cells from three indepen- dent experiments were included, and the time points C EFnsP3 G3BP1 eIF3b Merge at which SGs appeared/disappeared and nsP3 con- Biological replicate densates appeared were measured within each cell. Biological replicate Error bars correspond to SD. (D) U2OS cells were in- 1000 Unstressed ARS *** * ARS+CHX fected with CHIKV WT at MOI of 1. At 6 h postin- 800 fection (hpi), cells were fixed and immunostained for * *** nsP3 and indicated SG proteins. (E) U2OS cells 100 600 CHX transfected with GFP-tagged nsP3WT were either 400 80 unstressed, treated with 100 μg/mL cycloheximide Time (min) (CHX), 0.2 mM arsenite alone (ARS), or cotreated 60 200 **** with 0.2 mM arsenite and 100 μg/mL cycloheximide ARS 0 40 (ARS+CHX) for 30 min. Cells were then fixed and I II III immunostained for G3BP1 (red) and eIF3b (blue). 20 Sequence of events during Asterisks indicate untransfected cells. (F) Bar graph viral infection (Panel A) shows the percentage of GFP-positive cells with SGs ARS+CHX * * * * 0 % GFP-positive cells with SGs WT from three independent experiments. Error bars correspond to mean ± SD. (Scale bars, 10 μm.) The mosquito-borne alphaviruses, which cause a range of dis- cells and specifically regulates translation factor localization. To- eases from rashes and arthritis to encephalitis, induce SG forma- gether, these data argue that nsP3
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