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Article ; Online: The histone chaperone NASP maintains H3-H4 reservoirs in the early Drosophila embryo.

Tirgar, Reyhaneh / Davies, Jonathan P / Plate, Lars / Nordman, Jared T

2023 Volume 19, Issue 3, Page(s) e1010682

Abstract: Histones are essential for chromatin packaging, and histone supply must be tightly regulated as excess histones are toxic. To drive the rapid cell cycles of the early embryo, however, excess histones are maternally deposited. Therefore, soluble histones ... ...

Abstract	Histones are essential for chromatin packaging, and histone supply must be tightly regulated as excess histones are toxic. To drive the rapid cell cycles of the early embryo, however, excess histones are maternally deposited. Therefore, soluble histones must be buffered by histone chaperones, but the chaperone necessary to stabilize soluble H3-H4 pools in the Drosophila embryo has yet to be identified. Here, we show that CG8223, the Drosophila homolog of NASP, is a H3-H4-specific chaperone in the early embryo. We demonstrate that, while a NASP null mutant is viable in Drosophila, NASP is a maternal effect gene. Embryos laid by NASP mutant mothers have a reduced rate of hatching and show defects in early embryogenesis. Critically, soluble H3-H4 pools are degraded in embryos laid by NASP mutant mothers. Our work identifies NASP as the critical H3-H4 histone chaperone in the Drosophila embryo.
MeSH term(s)	Animals ; Histones/genetics ; Histones/metabolism ; Histone Chaperones/genetics ; Drosophila/genetics ; Drosophila/metabolism ; Chromatin ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism
Chemical Substances	Histones ; Histone Chaperones ; Chromatin ; Molecular Chaperones
Language	English
Publishing date	2023-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010682
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Comparative host interactomes of the SARS-CoV-2 nonstructural protein 3 and human coronavirus homologs.

Almasy, Katherine M / Davies, Jonathan P / Plate, Lars

bioRxiv : the preprint server for biology

2021

Abstract: Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of ... ...

Abstract	Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, non-structural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) dataset for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance nuclear protein important for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.
Language	English
Publishing date	2021-03-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.08.434440
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Article ; Online: Comparative Host Interactomes of the SARS-CoV-2 Nonstructural Protein 3 and Human Coronavirus Homologs.

Almasy, Katherine M / Davies, Jonathan P / Plate, Lars

Molecular & cellular proteomics : MCP

2021 Volume 20, Page(s) 100120

Abstract	Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold-like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, nonstructural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) data set for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance, nuclear protein import for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.
MeSH term(s)	Activating Transcription Factor 6/metabolism ; Coronavirus 229E, Human/metabolism ; Coronavirus 229E, Human/pathogenicity ; Coronavirus OC43, Human/metabolism ; Coronavirus OC43, Human/pathogenicity ; Coronavirus Papain-Like Proteases/genetics ; Coronavirus Papain-Like Proteases/metabolism ; Endoplasmic Reticulum-Associated Degradation ; HEK293 Cells ; Host-Pathogen Interactions/physiology ; Humans ; Middle East Respiratory Syndrome Coronavirus/metabolism ; Middle East Respiratory Syndrome Coronavirus/pathogenicity ; Protein Interaction Maps ; SARS-CoV-2/metabolism ; SARS-CoV-2/pathogenicity ; Unfolded Protein Response ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism
Chemical Substances	ATF6 protein, human ; Activating Transcription Factor 6 ; Nsp3 protein, Middle East respiratory syndrome coronavirus ; Viral Nonstructural Proteins ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; papain-like protease, SARS-CoV-2 (EC 3.4.22.2)
Language	English
Publishing date	2021-06-27
Publishing country	United States
Document type	Comparative Study ; 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.
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2021.100120
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Article: SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response.

Davies, Jonathan P / Sivadas, Athira / Keller, Katherine R / Wojcikiewicz, Richard J H / Plate, Lars

bioRxiv : the preprint server for biology

2023

Abstract: Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and ... ...

Abstract	Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and increasing protein folding capacity. While CoV nonstructural proteins (nsps) are essential for infection, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, a key driver of replication, on the UPR using quantitative proteomics to sensitively detect pathway-wide upregulation of effector proteins. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological ATF6 activation. To determine how nsp3.1 and nsp4 tune the UPR, their co-expression demonstrated that nsp3.1 suppresses nsp4-mediated PERK, but not ATF6 activation. Re-analysis of SARS-CoV-2 infection proteomics data revealed time-dependent activation of PERK targets early in infection, which subsequently fades. This temporal regulation suggests a role for nsp3 and nsp4 in tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic activation. This work furthers our understanding of CoV-host proteostasis interactions and highlights the power of proteomic methods for systems-level analysis of the UPR.
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.22.537917
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Article ; Online: BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels.

Han, Dongsheng / Schaffner, Samantha H / Davies, Jonathan P / Benton, Mary Lauren / Plate, Lars / Nordman, Jared T

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 39, Page(s) e2305092120

Abstract: Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3 (Bromodomain and WD repeat- ...

Abstract	Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3 (Bromodomain and WD repeat-containing protein 3), a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased H3K4me1 (H3 lysine 4 monomethylation) levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels but also causes a decrease in H3K4me3 (H3 lysine 4 trimethylation) levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific lysine demethylase 5 (KDM5/Lid), an enzyme that removes tri- and dimethyl marks from H3K4. Moreover, analysis of ChIP-seq (chromatin immunoprecipitation sequencing) data revealed that BRWD3 and KDM5 are significantly colocalized throughout the genome and H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.
MeSH term(s)	Chromatin ; Histone Code ; Lysine ; Methylation ; Protein Processing, Post-Translational ; Drosophila ; Animals
Chemical Substances	Chromatin ; Lysine (K3Z4F929H6) ; Lid protein, Drosophila (EC 1.14.11.-) ; BRWD3 protein, Drosophila
Language	English
Publishing date	2023-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2305092120
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Article: BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels.

Han, Dongsheng / Schaffner, Samantha H / Davies, Jonathan P / Lauren Benton, Mary / Plate, Lars / Nordman, Jared T

bioRxiv : the preprint server for biology

2023

Abstract	Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased in H3K4me1 levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels, but also causes a decrease in H3K4me3 levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from H3K4. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co- localized throughout the genome and that sites of H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.
Language	English
Publishing date	2023-03-28
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.28.534572
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Article ; Online: Expression of SARS-CoV-2 Nonstructural Proteins 3 and 4 Can Tune the Unfolded Protein Response in Cell Culture.

Davies, Jonathan P / Sivadas, Athira / Keller, Katherine R / Roman, Brynn K / Wojcikiewicz, Richard J H / Plate, Lars

Journal of proteome research

2023 Volume 23, Issue 1, Page(s) 356–367

Abstract: Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through the activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and ...

Abstract	Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through the activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and increasing protein folding capacity. While CoV nonstructural proteins (nsps) are essential for infection, little is known about the role of nsps in modulating the UPR. We characterized the impact of overexpression of SARS-CoV-2 nsp4, a key driver of replication, on the UPR in cell culture using quantitative proteomics to sensitively detect pathway-wide upregulation of effector proteins. We find that nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found that an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological ATF6 activation. To determine how nsp3.1 and nsp4 tune the UPR, their coexpression demonstrated that nsp3.1 suppresses nsp4-mediated PERK, but not ATF6 activation. Reanalysis of SARS-CoV-2 infection proteomics data revealed time-dependent activation of PERK targets early in infection, which subsequently fades. This temporal regulation suggests a role for nsp3 and nsp4 in tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic activation. This work furthers our understanding of CoV-host proteostasis interactions and highlights the power of proteomic methods for systems-level analysis of the UPR.
MeSH term(s)	Humans ; SARS-CoV-2 ; Proteomics ; COVID-19 ; Unfolded Protein Response ; Cell Culture Techniques
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.3c00600
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Article ; Online: Comparative host interactomes of the SARS-CoV-2 nonstructural protein 3 and human coronavirus homologs

Almasy, Katherine M / Davies, Jonathan P / Plate, Lars

bioRxiv

Abstract	Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, non-structural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) dataset for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance nuclear protein important for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.
Keywords	covid19
Language	English
Publishing date	2021-03-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.03.08.434440
Database	COVID19

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Article ; Online: SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response

Davies, Jonathan P / Sivadas, Athira / Keller, Katherine R / Wojcikiewicz, Richard JH / Plate, Lars

bioRxiv

Abstract: Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis pathways during infection through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR). The UPR regulates protein translation, increases ... ...

Abstract	Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis pathways during infection through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR). The UPR regulates protein translation, increases protein folding capacity and enhances endoplasmic reticulum (ER) biogenesis to alleviate ER stress caused by accumulation of misfolded proteins. CoVs depend on host machinery to generate large amounts of viral protein and manipulate ER-derived membranes to form double-membrane vesicles (DMVs), which serve as replication sites, making the UPR a key host pathway for CoVs to hijack. Despite the importance of CoV nonstructural proteins (nsps) in mediating replication, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, which is a key driver of DMV formation, on the UPR using quantitative proteomics. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological activation of the ATF6 pathway. To determine how nsp3.1 and nsp4 might tune the UPR in concert, both proteins were co-expressed demonstrating that nsp3.1 does not suppress nsp4-mediated ATF6 activation but does suppress PERK activation. A meta-analysis of SARS-CoV-2 infection proteomics data reveals a time-dependent activation of PERK protein markers early in infection, which subsequently fades. This temporal regulation suggests a role for nsps tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic PERK activation. This work furthers our understanding of CoV-host proteostasis interactions and identifies potential areas to target for anti-viral therapies.
Keywords	covid19
Language	English
Publishing date	2023-04-24
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.04.22.537917
Database	COVID19

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Article ; Online: Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles.

Hannon, Eilis / Dempster, Emma L / Davies, Jonathan P / Chioza, Barry / Blake, Georgina E T / Burrage, Joe / Policicchio, Stefania / Franklin, Alice / Walker, Emma M / Bamford, Rosemary A / Schalkwyk, Leonard C / Mill, Jonathan

BMC biology

2024 Volume 22, Issue 1, Page(s) 17

Abstract: Background: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived ... ...

Abstract	Background: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. Results: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer's disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. Conclusions: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.
MeSH term(s)	Female ; Pregnancy ; Infant, Newborn ; Humans ; DNA Methylation ; Epigenesis, Genetic ; Neuroglia ; Cerebral Cortex ; Neurons/metabolism
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/s12915-024-01827-y
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