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Article ; Online: Role of spatial patterning of N-protein interactions in SARS-CoV-2 genome packaging.

Seim, Ian / Roden, Christine A / Gladfelter, Amy S

2022 Volume 121, Issue 8, Page(s) 1580

Language	English
Publishing date	2022-04-07
Publishing country	United States
Document type	Published Erratum
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2022.03.034
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Article ; Online: Design considerations for analyzing protein translation regulation by condensates.

Roden, Christine A / Gladfelter, Amy S

RNA (New York, N.Y.)

2021 Volume 28, Issue 1, Page(s) 88–96

Abstract: One proposed role for biomolecular condensates that contain RNA is translation regulation. In several specific contexts, translation has been shown to be modulated by the presence of a phase-separating protein and under conditions which promote phase ... ...

Abstract	One proposed role for biomolecular condensates that contain RNA is translation regulation. In several specific contexts, translation has been shown to be modulated by the presence of a phase-separating protein and under conditions which promote phase separation, and likely many more await discovery. A powerful tool for determining the rules for condensate-dependent translation is the use of engineered RNA sequences, which can serve as reporters for translation efficiency. This Perspective will discuss design features to consider in engineering RNA reporters to determine the role of phase separation in translational regulation. Specifically, we will cover (i) how to engineer RNA sequence to recapitulate native protein/RNA interactions, (ii) the advantages and disadvantages for commonly used reporter RNA sequences, and (iii) important control experiments to distinguish between binding- and condensation-dependent translational repression. The goal of this review is to promote the design and application of faithful translation reporters to demonstrate a physiological role of biomolecular condensates in translation.
MeSH term(s)	Binding Sites ; Biomolecular Condensates/chemistry ; Biomolecular Condensates/metabolism ; Eukaryota ; Eukaryotic Cells/metabolism ; Fluorescent Antibody Technique/methods ; Genes, Reporter ; Genetic Engineering/methods ; Protein Binding ; Protein Biosynthesis ; Protein Folding ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins/chemistry ; Ribonucleoproteins/genetics ; Ribonucleoproteins/metabolism ; Ribosomes/genetics ; Ribosomes/metabolism
Chemical Substances	RNA, Messenger ; RNA-Binding Proteins ; Ribonucleoproteins
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079002.121
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Article: Role of spatial patterning of N-protein interactions in SARS-CoV-2 genome packaging.

Seim, Ian / Roden, Christine A / Gladfelter, Amy S

bioRxiv : the preprint server for biology

2021

Abstract: Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral sub-genomic fragments. Some viruses use specific packaging signals, which are conserved sequence/structure motifs present only in the full- ... ...

Abstract	Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral sub-genomic fragments. Some viruses use specific packaging signals, which are conserved sequence/structure motifs present only in the full-length genome. Recent work has shown that viral proteins important for packaging can undergo liquid-liquid phase separation (LLPS), where one or two viral nucleic acid binding proteins condense with the genome. The compositional simplicity of viral components lends itself well to theoretical modeling compared to more complex cellular organelles. Viral LLPS can be limited to one or two viral proteins and a single genome that is enriched in LLPS-promoting features. In our previous study, we observed that LLPS-promoting sequences of SARS-CoV-2 are located at the 5' and 3' ends of the genome, whereas the middle of the genome is predicted to consist mostly of solubilizing elements. Is this arrangement sufficient to drive single genome packaging, genome compaction, and genome cyclization? We addressed these questions using a coarse-grained polymer model, LASSI, to study the LLPS of nucleocapsid protein with RNA sequences that either promote LLPS or solubilization. With respect to genome cyclization, we find the most optimal arrangement restricts LLPS-promoting elements to the 5' and 3' ends of the genome, consistent with the native spatial patterning. Genome compaction is enhanced by clustered LLPS-promoting binding sites, while single genome packaging is most efficient when binding sites are distributed throughout the genome. These results suggest that many and variably positioned LLPS-promoting signals can support packaging in the absence of a singular packaging signal which argues against necessity of such a feature. We hypothesize that this model should be generalizable to multiple viruses as well as cellular organelles like paraspeckles, which enrich specific, long RNA sequences in a defined arrangement.
Language	English
Publishing date	2021-04-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.01.06.425605
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Article ; Online: Role of spatial patterning of N-protein interactions in SARS-CoV-2 genome packaging.

Seim, Ian / Roden, Christine A / Gladfelter, Amy S

Biophysical journal

2021 Volume 120, Issue 14, Page(s) 2771–2784

Abstract: Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral subgenomic fragments. Some viruses use specific packaging signals, which are conserved sequence or structure motifs present only in the full- ... ...

Abstract	Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral subgenomic fragments. Some viruses use specific packaging signals, which are conserved sequence or structure motifs present only in the full-length genome. Recent work has shown that viral proteins important for packaging can undergo liquid-liquid phase separation (LLPS), in which one or two viral nucleic acid binding proteins condense with the genome. The compositional simplicity of viral components lends itself well to theoretical modeling compared with more complex cellular organelles. Viral LLPS can be limited to one or two viral proteins and a single genome that is enriched in LLPS-promoting features. In our previous study, we observed that LLPS-promoting sequences of severe acute respiratory syndrome coronavirus 2 are located at the 5' and 3' ends of the genome, whereas the middle of the genome is predicted to consist mostly of solubilizing elements. Is this arrangement sufficient to drive single genome packaging, genome compaction, and genome cyclization? We addressed these questions using a coarse-grained polymer model, LASSI, to study the LLPS of nucleocapsid protein with RNA sequences that either promote LLPS or solubilization. With respect to genome cyclization, we find the most optimal arrangement restricts LLPS-promoting elements to the 5' and 3' ends of the genome, consistent with the native spatial patterning. Genome compaction is enhanced by clustered LLPS-promoting binding sites, whereas single genome packaging is most efficient when binding sites are distributed throughout the genome. These results suggest that many and variably positioned LLPS-promoting signals can support packaging in the absence of a singular packaging signal which argues against necessity of such a feature. We hypothesize that this model should be generalizable to multiple viruses as well as cellular organelles such as paraspeckles, which enrich specific long RNA sequences in a defined arrangement.
Language	English
Publishing date	2021-06-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2021.06.018
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Article ; Online: Role of spatial patterning of N-protein interactions in SARS-CoV-2 genome packaging

Seim, Ian / Roden, Christine / Gladfelter, Amy

bioRxiv

Abstract	Viruses must efficiently and specifically package their genomes while excluding cellular nucleic acids and viral sub-genomic fragments. Some viruses use specific packaging signals, which are conserved sequence/structure motifs present only in the full-length genome. Recent work has shown that viral proteins important for packaging can undergo liquid-liquid phase separation (LLPS), where one or two viral nucleic acid binding proteins condense with the genome. The compositional simplicity of viral components lends itself well to theoretical modeling compared to more complex cellular organelles. Viral LLPS can be limited to one or two viral proteins and a single genome that is enriched in LLPS-promoting features. In our previous study, we observed that LLPS-promoting sequences of SARS-CoV-2 are located at the 59 and 39 ends of the genome, whereas the middle of the genome is predicted to consist mostly of solubilizing elements. Is this arrangement sufficient to drive single genome packaging, genome compaction, and genome cyclization? We addressed these questions using a coarse-grained polymer model, LASSI, to study the LLPS of nucleocapsid protein with RNA sequences that either promote LLPS or solubilization. With respect to genome compaction and cyclization, we find the most optimal arrangement restricts LLPS-promoting elements to the 59 and 39 ends of the genome, consistent with the native spatial patterning. Single genome packaging is possible for diverse arrangements of LLPS-promoting sequences in the genome, but only in limited conditions at the edge of the phase boundary. These results suggest that many and variably positioned LLPS promoting signals can support packaging in the absence of a singular packaging signal which argues against necessity of such a feature. We hypothesize that this model should be generalizable to multiple viruses as well as cellular organelles like paraspeckles, which enrich specific, long RNA sequences in a defined order.
Keywords	covid19
Language	English
Publishing date	2021-01-06
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.01.06.425605
Database	COVID19

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Article: Human tear film protein sampling using soft contact lenses.

Roden, Robert K / Zuniga, Nathan / Wright, Joshua C / Parkinson, David H / Jiang, Fangfang / Patil, Leena M / Burlett, Rebecca S / Nitz, Alyssa A / Rogers, Joshua J / Pittman, Jarett T / Virgin, Kenneth L / Ackroyd, P Christine / Payne, Samuel H / Price, John C / Christensen, Kenneth A

Clinical proteomics

2024 Volume 21, Issue 1, Page(s) 23

Abstract: Background: Human tear protein biomarkers are useful for detecting ocular and systemic diseases. Unfortunately, existing tear film sampling methods (Schirmer strip; SS and microcapillary tube; MCT) have significant drawbacks, such as pain, risk of ... ...

Abstract	Background: Human tear protein biomarkers are useful for detecting ocular and systemic diseases. Unfortunately, existing tear film sampling methods (Schirmer strip; SS and microcapillary tube; MCT) have significant drawbacks, such as pain, risk of injury, sampling difficulty, and proteomic disparities between methods. Here, we present an alternative tear protein sampling method using soft contact lenses (SCLs). Results: We optimized the SCL protein sampling in vitro and performed in vivo studies in 6 subjects. Using Etafilcon A SCLs and 4M guanidine-HCl for protein removal, we sampled an average of 60 ± 31 µg of protein per eye. We also performed objective and subjective assessments of all sampling methods. Signs of irritation post-sampling were observed with SS but not with MCT and SCLs. Proteomic analysis by mass spectrometry (MS) revealed that all sampling methods resulted in the detection of abundant tear proteins. However, smaller subsets of unique and shared proteins were identified, particularly for SS and MCT. Additionally, there was no significant intrasubject variation between MCT and SCL sampling. Conclusions: These experiments demonstrate that SCLs are an accessible tear-sampling method with the potential to surpass current methods in sampling basal tears.
Language	English
Publishing date	2024-03-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2205154-5
ISSN	1542-6416
ISSN	1542-6416
DOI	10.1186/s12014-024-09475-8
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Article ; Online: Fatal Infections Differentially Involve Allograft and Native Lungs in Single Lung Transplant Recipients.

Villalba, Julian A / Cheek-Norgan, E Heidi / Johnson, Tucker F / Yi, Eunhee S / Boland, Jennifer M / Aubry, Marie-Christine / Pennington, Kelly M / Scott, John P / Roden, Anja C

Archives of pathology & laboratory medicine

2023

Abstract: Context.—: Respiratory infections complicate lung transplantation and increase the risk of allograft dysfunction. Allograft lungs may have different susceptibilities to infection than native lungs, potentially leading to different disease severity in ... ...

Abstract	Context.—: Respiratory infections complicate lung transplantation and increase the risk of allograft dysfunction. Allograft lungs may have different susceptibilities to infection than native lungs, potentially leading to different disease severity in lungs of single lung transplant recipients (SLTRs). Objective.—: To study whether infections affect allograft and native lungs differently in SLTRs but similarly in double LTRs (DLTRs). Design.—: Using an institutional database of LTRs, medical records were searched, chest computed tomography studies were systematically reviewed, and histopathologic features were recorded per lung lobe and graded semiquantitatively. A multilobar-histopathology score (MLHS) including histopathologic data from each lung and a bilateral ratio (MLHSratio) comparing histopathologies between both lungs were calculated in SLTRs and compared to DLTRs. Results.—: Six SLTRs died of infection involving the lungs. All allografts showed multifocal histopathologic evidence of infection, but at least 1 lobe of the native lung was uninvolved. In all 5 DLTRs except 1, histopathologic evidence of infection was seen in all lung lobes. On computed tomography, multifocal ground-glass and/or nodular opacities were found in a bilateral distribution in all DLTRs but in only 2 of 6 SLTRs. In SLTRs, the MLHSAllograft was higher than MLHSNative (P = .02). The MLHSratio values of SLTR and DLTR were significantly different (P < .001). Conclusions.—: Allograft and native lungs appear to harbor different susceptibilities to infections. The results are important for the management of LTRs.
Language	English
Publishing date	2023-09-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2023-0227-OA
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Article ; Online: RNA contributions to the form and function of biomolecular condensates.

Roden, Christine / Gladfelter, Amy S

Nature reviews. Molecular cell biology

2020 Volume 22, Issue 3, Page(s) 183–195

Abstract: Biomolecular condensation partitions cellular contents and has important roles in stress responses, maintaining homeostasis, development and disease. Many nuclear and cytoplasmic condensates are rich in RNA and RNA-binding proteins (RBPs), which undergo ... ...

Abstract	Biomolecular condensation partitions cellular contents and has important roles in stress responses, maintaining homeostasis, development and disease. Many nuclear and cytoplasmic condensates are rich in RNA and RNA-binding proteins (RBPs), which undergo liquid-liquid phase separation (LLPS). Whereas the role of RBPs in condensates has been well studied, less attention has been paid to the contribution of RNA to LLPS. In this Review, we discuss the role of RNA in biomolecular condensation and highlight considerations for designing condensate reconstitution experiments. We focus on RNA properties such as composition, length, structure, modifications and expression level. These properties can modulate the biophysical features of native condensates, including their size, shape, viscosity, liquidity, surface tension and composition. We also discuss the role of RNA-protein condensates in development, disease and homeostasis, emphasizing how their properties and function can be determined by RNA. Finally, we discuss the multifaceted cellular functions of biomolecular condensates, including cell compartmentalization through RNA transport and localization, supporting catalytic processes, storage and inheritance of specific molecules, and buffering noise and responding to stress.
MeSH term(s)	Animals ; Cell Physiological Phenomena ; Chemical Phenomena ; Humans ; Macromolecular Substances/chemistry ; Macromolecular Substances/metabolism ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/metabolism ; Multiprotein Complexes/physiology ; Protein Aggregates/physiology ; RNA/physiology ; RNA-Binding Proteins/metabolism ; RNA-Binding Proteins/physiology
Chemical Substances	Macromolecular Substances ; Multiprotein Complexes ; Protein Aggregates ; RNA-Binding Proteins ; RNA (63231-63-0)
Language	English
Publishing date	2020-07-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-020-0264-6
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Article ; Online: A case-control autopsy series of liver pathology associated with novel coronavirus disease (COVID-19).

Righi, Fabiola A / Vander Heide, Richard S / Graham, Rondell P / Aubry, Marie Christine / Trejo-Lopez, Jorge A / Bois, Melanie C / Roden, Anja C / Reichard, Ross / Maleszewski, Joseph J / Alexander, Mariam P / Quinton, Reade A / Jenkins, Sarah M / Hartley, Christopher P / Hagen, Catherine E

Annals of diagnostic pathology

2023 Volume 68, Page(s) 152240

Abstract: Background: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. ... ...

Abstract	Background: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19. Methods: Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA. Results: 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue. Conclusions: The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.
MeSH term(s)	Humans ; Aged ; SARS-CoV-2 ; COVID-19/pathology ; RNA, Viral/analysis ; Alcoholism/complications ; Alcoholism/pathology ; Liver/pathology ; Inflammation/pathology ; Autopsy ; Case-Control Studies
Chemical Substances	RNA, Viral
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	1440011-x
ISSN	1532-8198 ; 1092-9134
ISSN (online)	1532-8198
ISSN	1092-9134
DOI	10.1016/j.anndiagpath.2023.152240
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Article ; Online: Double-stranded RNA drives SARS-CoV-2 nucleocapsid protein to undergo phase separation at specific temperatures.

Roden, Christine A / Dai, Yifan / Giannetti, Catherine A / Seim, Ian / Lee, Myungwoon / Sealfon, Rachel / McLaughlin, Grace A / Boerneke, Mark A / Iserman, Christiane / Wey, Samuel A / Ekena, Joanne L / Troyanskaya, Olga G / Weeks, Kevin M / You, Lingchong / Chilkoti, Ashutosh / Gladfelter, Amy S

Nucleic acids research

2022 Volume 50, Issue 14, Page(s) 8168–8192

Abstract: Nucleocapsid protein (N-protein) is required for multiple steps in betacoronaviruses replication. SARS-CoV-2-N-protein condenses with specific viral RNAs at particular temperatures making it a powerful model for deciphering RNA sequence specificity in ... ...

Abstract	Nucleocapsid protein (N-protein) is required for multiple steps in betacoronaviruses replication. SARS-CoV-2-N-protein condenses with specific viral RNAs at particular temperatures making it a powerful model for deciphering RNA sequence specificity in condensates. We identify two separate and distinct double-stranded, RNA motifs (dsRNA stickers) that promote N-protein condensation. These dsRNA stickers are separately recognized by N-protein's two RNA binding domains (RBDs). RBD1 prefers structured RNA with sequences like the transcription-regulatory sequence (TRS). RBD2 prefers long stretches of dsRNA, independent of sequence. Thus, the two N-protein RBDs interact with distinct dsRNA stickers, and these interactions impart specific droplet physical properties that could support varied viral functions. Specifically, we find that addition of dsRNA lowers the condensation temperature dependent on RBD2 interactions and tunes translational repression. In contrast RBD1 sites are sequences critical for sub-genomic (sg) RNA generation and promote gRNA compression. The density of RBD1 binding motifs in proximity to TRS-L/B sequences is associated with levels of sub-genomic RNA generation. The switch to packaging is likely mediated by RBD1 interactions which generate particles that recapitulate the packaging unit of the virion. Thus, SARS-CoV-2 can achieve biochemical complexity, performing multiple functions in the same cytoplasm, with minimal protein components based on utilizing multiple distinct RNA motifs that control N-protein interactions.
MeSH term(s)	Binding Sites ; Coronavirus Nucleocapsid Proteins/chemistry ; Phosphoproteins/chemistry ; RNA, Double-Stranded/genetics ; RNA, Viral/genetics ; RNA-Binding Proteins/metabolism ; SARS-CoV-2/genetics ; Temperature
Chemical Substances	Coronavirus Nucleocapsid Proteins ; Phosphoproteins ; RNA, Double-Stranded ; RNA, Viral ; RNA-Binding Proteins ; nucleocapsid phosphoprotein, SARS-CoV-2
Language	English
Publishing date	2022-08-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac596
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