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Article ; Online: Clip for studying protein-RNA interactions that regulate virus replication.

Shema Mugisha, Christian / Tenneti, Kasyap / Kutluay, Sebla B

2019 Volume 183, Page(s) 84–92

Abstract: Viral and cellular RNA-binding proteins regulate numerous key steps in the replication of diverse virus genera. Viruses efficiently co-opt the host cell machinery for purposes such as transcription, splicing and subcellular localization of viral genomes. ...

Abstract	Viral and cellular RNA-binding proteins regulate numerous key steps in the replication of diverse virus genera. Viruses efficiently co-opt the host cell machinery for purposes such as transcription, splicing and subcellular localization of viral genomes. Though viral RNAs often need to resemble cellular RNAs to effectively utilize the cellular machinery, they still retain unique sequence and structural features for recognition by viral proteins for processes such as RNA polymerization, RNA export and selective packaging into virus particles. While beneficial for virus replication, distinct features of viral nucleic acids can also be recognized as foreign by several host defense proteins. Development of the crosslinking immunoprecipitation coupled with sequencing (CLIP) approach has allowed the study of viral and cellular RNA binding proteins that regulate critical aspects of viral replication in unprecedented detail. By combining immunoprecipitation of covalently crosslinked protein-RNA complexes with high-throughput sequencing, CLIP provides a global account of RNA sequences bound by RNA-binding proteins of interest in physiological settings and at near-nucleotide resolution. Here, we describe the step-by-step application of the CLIP methodology within the context of two cellular splicing regulatory proteins, hnRNP A1 and hnRNP H1 that regulate HIV-1 splicing. In principle, this versatile protocol can be applied to many other viral and cellular RNA-binding proteins.
MeSH term(s)	Chromatin Immunoprecipitation Sequencing/methods ; HEK293 Cells ; HIV-1/genetics ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism ; Humans ; RNA Splicing ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Virus Replication
Chemical Substances	Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H ; RNA, Viral
Language	English
Publishing date	2019-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2019.11.011
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Emergence of Compensatory Mutations Reveals the Importance of Electrostatic Interactions between HIV-1 Integrase and Genomic RNA.

Shema Mugisha, Christian / Dinh, Tung / Kumar, Abhishek / Tenneti, Kasyap / Eschbach, Jenna E / Davis, Keanu / Gifford, Robert / Kvaratskhelia, Mamuka / Kutluay, Sebla B

mBio

2022 Volume 13, Issue 5, Page(s) e0043122

Abstract: HIV-1 integrase (IN) has a noncatalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Class II IN substitutions inhibit IN-gRNA binding and result in the formation of virions with aberrant morphologies marked by ... ...

Abstract	HIV-1 integrase (IN) has a noncatalytic function in virion maturation through its binding to the viral RNA genome (gRNA). Class II IN substitutions inhibit IN-gRNA binding and result in the formation of virions with aberrant morphologies marked by mislocalization of the gRNA between the capsid lattice and the lipid envelope. These viruses are noninfectious due to a block at an early reverse transcription stage in target cells. HIV-1 IN utilizes basic residues within its C-terminal domain (CTD) to bind to the gRNA; however, the molecular nature of how these residues mediate gRNA binding and whether other regions of IN are involved remain unknown. To address this, we have isolated compensatory substitutions in the background of a class II IN mutant virus bearing R269A/K273A substitutions within the IN-CTD. We found that the nearby D256N and D270N compensatory substitutions restored the ability of IN to bind gRNA and led to the formation of mature infectious virions. Reinstating the local positive charge of the IN-CTD through individual D256R, D256K, D278R, and D279R substitutions was sufficient to specifically restore IN-gRNA binding and reverse transcription for the IN R269A/K273A as well as the IN R262A/R263A class II mutants. Structural modeling suggested that compensatory substitutions in the D256 residue created an additional interaction interface for gRNA binding, whereas other substitutions acted locally within the unstructured C-terminal tail of IN. Taken together, our findings highlight the essential role of CTD in gRNA binding and reveal the importance of pliable electrostatic interactions between the IN-CTD and the gRNA.
MeSH term(s)	RNA, Viral/genetics ; RNA, Viral/metabolism ; Virus Assembly/genetics ; Static Electricity ; Aspartic Acid/metabolism ; HIV-1/physiology ; Virion/genetics ; Virion/metabolism ; Mutation ; Genomics ; Lipids
Chemical Substances	p31 integrase protein, Human immunodeficiency virus 1 (YY6481J2FF) ; RNA, Viral ; Aspartic Acid (30KYC7MIAI) ; Lipids
Language	English
Publishing date	2022-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.00431-22
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Clip for studying protein-RNA interactions that regulate virus replication

Shema Mugisha, Christian / Tenneti, Kasyap / Kutluay, Sebla B

Methods. 2019 Nov. 19,

2019

Abstract	Viral and cellular RNA-binding proteins regulate numerous key steps in the replication of diverse virus genera. Viruses efficiently co-opt the host cell machinery for purposes such as transcription, splicing and subcellular localization of viral genomes. Though viral RNAs often need to resemble cellular RNAs to effectively utilize the cellular machinery, they still retain unique sequence and structural features for recognition by viral proteins for processes such as RNA polymerization, RNA export and selective packaging into virus particles. While beneficial for virus replication, distinct features of viral nucleic acids can also be recognized as foreign by several host defense proteins. Development of the crosslinking immunoprecipitation coupled with sequencing (CLIP) approach has allowed the study of viral and cellular RNA binding proteins that regulate critical aspects of viral replication in unprecedented detail. By combining immunoprecipitation of covalently crosslinked protein-RNA complexes with high-throughput sequencing, CLIP provides a global account of RNA sequences bound by RNA-binding proteins of interest in physiological settings and at near-nucleotide resolution. Here, we describe the step-by-step application of the CLIP methodology within the context of two cellular splicing regulatory proteins, hnRNP A1 and hnRNP H1 that regulate HIV-1 splicing. In principle, this versatile protocol can be applied to many other viral and cellular RNA-binding proteins.
Keywords	Human immunodeficiency virus 1 ; RNA ; RNA transport ; RNA-binding proteins ; chemical bonding ; crosslinking ; genome ; high-throughput nucleotide sequencing ; nucleotide sequences ; packaging ; polymerization ; precipitin tests ; regulatory proteins ; transcription (genetics) ; viral proteins ; virion ; virus replication ; viruses
Language	English
Dates of publication	2019-1119
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2019.11.011
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Translational Landscape of SARS-CoV-2-infected Cells Reveals Suppression of Innate Immune Genes.

Puray-Chavez, Maritza / Lee, Nakyung / Tenneti, Kasyap / Wang, Yiqing / Vuong, Hung R / Liu, Yating / Horani, Amjad / Huang, Tao / Gunsten, Sean P / Case, James B / Yang, Wei / Diamond, Michael S / Brody, Steven L / Dougherty, Joseph / Kutluay, Sebla B

mBio

2022 Volume 13, Issue 3, Page(s) e0081522

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2-infected model cell lines and primary airway cells grown at an air- ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2-infected model cell lines and primary airway cells grown at an air-liquid interface to gain a deeper understanding of the translationally regulated events in response to virus replication. We found that SARS-CoV-2 mRNAs dominate the cellular mRNA pool but are not more efficiently translated than cellular mRNAs. SARS-CoV-2 utilized a highly efficient ribosomal frameshifting strategy despite notable accumulation of ribosomes within the slippery sequence on the frameshifting element. In a highly permissive cell line model, although SARS-CoV-2 infection induced the transcriptional upregulation of numerous chemokine, cytokine, and interferon-stimulated genes, many of these mRNAs were not translated efficiently. The impact of SARS-CoV-2 on host mRNA translation was more subtle in primary cells, with marked transcriptional and translational upregulation of inflammatory and innate immune responses and downregulation of processes involved in ciliated cell function. Together, these data reveal the key role of mRNA translation in SARS-CoV-2 replication and highlight unique mechanisms for therapeutic development.
MeSH term(s)	COVID-19/genetics ; Humans ; Immunity, Innate ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Ribosomes/metabolism ; SARS-CoV-2/genetics
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2022-05-23
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.00815-22
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The translational landscape of SARS-CoV-2 and infected cells.

bioRxiv : the preprint server for biology

2021

Abstract: SARS-CoV-2 utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2 infected model cell lines and primary airway cells grown at the air-liquid interface to gain a deeper understanding of ... ...

Abstract	SARS-CoV-2 utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2 infected model cell lines and primary airway cells grown at the air-liquid interface to gain a deeper understanding of the translationally regulated events in response to virus replication. We find that SARS-CoV-2 mRNAs dominate the cellular mRNA pool but are not more efficiently translated than cellular mRNAs. SARS-CoV-2 utilized a highly efficient ribosomal frameshifting strategy in comparison to HIV-1, suggesting utilization of distinct structural elements. In the highly permissive cell models, although SARS-CoV-2 infection induced the transcriptional upregulation of numerous chemokines, cytokines and interferon stimulated genes, many of these mRNAs were not translated efficiently. Impact of SARS-CoV-2 on host mRNA translation was more subtle in primary cells, with marked transcriptional and translational upregulation of inflammatory and innate immune responses and downregulation of processes involved in ciliated cell function. Together, these data reveal the key role of mRNA translation in SARS-CoV-2 replication and highlight unique mechanisms for therapeutic development.
Keywords	covid19
Language	English
Publishing date	2021-10-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.11.03.367516
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Article ; Online: Genome-Wide Analysis of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) Binding to HIV-1 RNA Reveals a Key Role for hnRNP H1 in Alternative Viral mRNA Splicing.

Kutluay, Sebla B / Emery, Ann / Penumutchu, Srinivasa R / Townsend, Dana / Tenneti, Kasyap / Madison, Michaela K / Stukenbroeker, Amanda M / Powell, Chelsea / Jannain, David / Tolbert, Blanton S / Swanstrom, Ronald I / Bieniasz, Paul D

Journal of virology

2019 Volume 93, Issue 21

Abstract: Alternative splicing of HIV-1 mRNAs increases viral coding potential and controls the levels and timing of gene expression. HIV-1 splicing is regulated in part by heterogeneous nuclear ribonucleoproteins (hnRNPs) and their viral target sequences, which ... ...

Abstract	Alternative splicing of HIV-1 mRNAs increases viral coding potential and controls the levels and timing of gene expression. HIV-1 splicing is regulated in part by heterogeneous nuclear ribonucleoproteins (hnRNPs) and their viral target sequences, which typically repress splicing when studied outside their native viral context. Here, we determined the location and extent of hnRNP binding to HIV-1 mRNAs and their impact on splicing in a native viral context. Notably, hnRNP A1, hnRNP A2, and hnRNP B1 bound to many dispersed sites across viral mRNAs. Conversely, hnRNP H1 bound to a few discrete purine-rich sequences, a finding that was mirrored
MeSH term(s)	Alternative Splicing ; Binding Sites ; Gene Expression Regulation, Viral ; HIV-1/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/chemistry ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group F-H/metabolism ; Humans ; Protein Conformation ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Regulatory Sequences, Nucleic Acid ; vif Gene Products, Human Immunodeficiency Virus/genetics ; vif Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Heterogeneous-Nuclear Ribonucleoprotein Group F-H ; RNA Precursors ; RNA, Messenger ; RNA, Viral ; vif Gene Products, Human Immunodeficiency Virus ; vif protein, Human immunodeficiency virus 1
Language	English
Publishing date	2019-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01048-19
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Article ; Online: The translational landscape of SARS-CoV-2 and infected cells

Puray-Chavez, Maritza / Tenneti, Kasyap / Vuong, Hung R. / Lee, Nakyung / Liu, Yating / Horani, Amjad / Huang, Tao / Case, James B. / Yang, Wei / Diamond, Michael S. / Brody, Steven L. / Dougherty, Joseph / Kutluay, Sebla B.

bioRxiv

Abstract: SARS-CoV-2, a betacoronavirus with a positive-sense RNA genome, has caused the ongoing COVID-19 pandemic. Although a large number of transcriptional profiling studies have been conducted in SARS-CoV-2 infected cells, little is known regarding the ... ...

Abstract	SARS-CoV-2, a betacoronavirus with a positive-sense RNA genome, has caused the ongoing COVID-19 pandemic. Although a large number of transcriptional profiling studies have been conducted in SARS-CoV-2 infected cells, little is known regarding the translational landscape of host and viral proteins. Here, using ribosome profiling in SARS-CoV-2-infected cells, we identify structural elements that regulate viral gene expression, alternative translation initiation events, as well as host responses regulated by mRNA translation. We found that the ribosome density was low within the SARS-CoV-2 frameshifting element but high immediately downstream, which suggests the utilization of a highly efficient ribosomal frameshifting strategy. In SARS-CoV-2-infected cells, although many chemokine, cytokine and interferon stimulated genes were upregulated at the mRNA level, they were not translated efficiently, suggesting a translational block that disarms host innate host responses. Together, these data reveal the key role of mRNA translation in SARS-CoV-2 replication and highlight unique mechanisms for therapeutic development.
Keywords	covid19
Language	English
Publishing date	2020-11-05
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.11.03.367516
Database	COVID19

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Article ; Online: Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell.

Puray-Chavez, Maritza / LaPak, Kyle M / Schrank, Travis P / Elliott, Jennifer L / Bhatt, Dhaval P / Agajanian, Megan J / Jasuja, Ria / Lawson, Dana Q / Davis, Keanu / Rothlauf, Paul W / Liu, Zhuoming / Jo, Heejoon / Lee, Nakyung / Tenneti, Kasyap / Eschbach, Jenna E / Shema Mugisha, Christian / Cousins, Emily M / Cloer, Erica W / Vuong, Hung R /

VanBlargan, Laura A / Bailey, Adam L / Gilchuk, Pavlo / Crowe, James E / Diamond, Michael S / Hayes, D Neil / Whelan, Sean P J / Horani, Amjad / Brody, Steven L / Goldfarb, Dennis / Major, M Ben / Kutluay, Sebla B

Cell reports

2021 Volume 36, Issue 2, Page(s) 109364

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
MeSH term(s)	Amino Acid Substitution ; Angiotensin-Converting Enzyme 2 ; Animals ; Antibodies, Monoclonal/immunology ; Antibodies, Viral/immunology ; COVID-19/immunology ; COVID-19/metabolism ; Cell Cycle ; Cell Line, Tumor ; Chlorocebus aethiops ; Gene Expression Profiling ; Heparitin Sulfate/metabolism ; Humans ; Interferon Type I/metabolism ; Interferon-Induced Helicase, IFIH1/metabolism ; Models, Biological ; Protein Binding ; Protein Domains ; Proteomics ; Receptors, Virus/metabolism ; SARS-CoV-2 ; Serine Endopeptidases/metabolism ; Signal Transduction ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Vero Cells ; Virus Internalization ; Virus Replication
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Viral ; Interferon Type I ; Receptors, Virus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Heparitin Sulfate (9050-30-0) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-) ; IFIH1 protein, human (EC 3.6.1.-) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13)
Language	English
Publishing date	2021-06-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2021.109364
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell.

Puray-Chavez, Maritza / LaPak, Kyle M / Schrank, Travis P / Elliott, Jennifer L / Bhatt, Dhaval P / Agajanian, Megan J / Jasuja, Ria / Lawson, Dana Q / Davis, Keanu / Rothlauf, Paul W / Jo, Heejoon / Lee, Nakyung / Tenneti, Kasyap / Eschbach, Jenna E / Mugisha, Christian Shema / Vuong, Hung R / Bailey, Adam L / Hayes, D Neil / Whelan, Sean P J /

Horani, Amjad / Brody, Steven L / Goldfarb, Dennis / Major, M Ben / Kutluay, Sebla B

bioRxiv : the preprint server for biology

2021

Abstract: ... ...

Abstract	Established
Language	English
Publishing date	2021-03-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.01.433431
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Article ; Online: Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Puray-Chavez, Maritza / Lapak, Kyle M / Schrank, Travis P. / Elliott, Jennifer L / Bhatt, Dhaval P / Agajanian, Megan J / Jasuja, Ria / Lawson, Dana Q / Davis, Keanu / Rothlauf, Paul W / Jo, Heejoon / Lee, Nakyung / Tenneti, Kasyap / Eschbach, Jenna E / Shema Mugisha, Christian / Vuong, Hung R / Bailey, Adam L / Hayes, D. Neil / Whelan, Sean P.J. /

Horani, Amjad / Brody, Steven L / Goldfarb, Dennis / Major, M. Ben / Kutluay, Sebla B

bioRxiv

Abstract: Established in vitro models for SARS-CoV-2 infection are limited and include cell lines of non-human origin and those engineered to overexpress ACE2, the cognate host cell receptor. We identified human H522 lung adenocarcinoma cells as naturally ... ...

Abstract	Established in vitro models for SARS-CoV-2 infection are limited and include cell lines of non-human origin and those engineered to overexpress ACE2, the cognate host cell receptor. We identified human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of ACE2. Infection of H522 cells required the SARS-CoV-2 spike protein, though in contrast to ACE2-dependent models, spike alone was not sufficient for H522 infection. Temporally resolved transcriptomic and proteomic profiling revealed alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type-I interferon signaling. Focused chemical screens point to important roles for clathrin-mediated endocytosis and endosomal cathepsins in SARS-CoV-2 infection of H522 cells. These findings imply the utilization of an alternative SARS-CoV-2 host cell receptor which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
Keywords	covid19
Language	English
Publishing date	2021-03-01
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.03.01.433431
Database	COVID19

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