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Book ; Online: Snapshots of the influenza virus transcription-replication machine in action and implications for anti-viral drug discovery

Cusack, Stephen

2020

Abstract: Influenza and SARS-CoV-2 both have single-stranded RNA as their genetic material. Although they are members of very different families of RNA viruses, they each possess an evolutionary-related RNA-dependent-RNA polymerase that transcribes and replicates ... ...

Abstract	Influenza and SARS-CoV-2 both have single-stranded RNA as their genetic material. Although they are members of very different families of RNA viruses, they each possess an evolutionary-related RNA-dependent-RNA polymerase that transcribes and replicates the viral RNA genome. Transcription is the process whereby the polymerase uses the genome as template to synthesize viral messenger RNA (mRNA), which directs the infected cell to produce viral proteins, whereas replication generates multiple, exact genome copies that are packaged into progeny virions. Because the polymerase is essential for the replicative cycle of the virus, it is a target of choice for antiviral drugs. Influenza RNA-dependent-RNA polymerase, which is a large, flexible complex of three distinct protein chains, transcribes the viral genome using unique mechanisms. Using state-of-the-art X-ray crystallography and electron cryo-microscopy we have obtained atomic resolution snapshots of influenza polymerase in action during the initiation, elongation and termination steps of the mRNA synthesis cycle, enabling the complete mechanism of transcription to be elucidated. Our work has underpinned the development by others of various small molecule inhibitors that target different binding sites on the influenza polymerase, one of which has recently been approved for clinical use in some countries. I will discuss whether newly developed anti-influenza drugs targeting the polymerase could also be useful against other RNA viruses, including SARS-CoV-2. Password: 271059
Keywords	CERN Colloquium ; covid19
Subject code	612 ; 570
Language	English
Publishing country	ch
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural and functional analysis of the minimal orthomyxovirus-like polymerase of Tilapia Lake Virus from the highly diverged Amnoonviridae family.

Arragain, Benoit / Pelosse, Martin / Thompson, Albert / Cusack, Stephen

Nature communications

2023 Volume 14, Issue 1, Page(s) 8145

Abstract: Tilapia Lake Virus (TiLV), a recently discovered pathogen of tilapia fish, belongs to the Amnoonviridae family from the Articulavirales order. Its ten genome segments have characteristic conserved ends and encode proteins with no known homologues, apart ... ...

Abstract	Tilapia Lake Virus (TiLV), a recently discovered pathogen of tilapia fish, belongs to the Amnoonviridae family from the Articulavirales order. Its ten genome segments have characteristic conserved ends and encode proteins with no known homologues, apart from the segment 1, which encodes an orthomyxo-like RNA-dependent-RNA polymerase core subunit. Here we show that segments 1-3 encode respectively the PB1, PB2 and PA-like subunits of an active heterotrimeric polymerase that maintains all domains found in the distantly related influenza polymerase, despite an unprecedented overall size reduction of 40%. Multiple high-resolution cryo-EM structures of TiLV polymerase in pre-initiation, initiation and active elongation states, show how it binds the vRNA and cRNA promoters and performs RNA synthesis, with both transcriptase and replicase configurations being characterised. However, the highly truncated endonuclease-like domain appears inactive and the putative cap-binding domain is autoinhibited, emphasising that many functional aspects of TiLV polymerase remain to be elucidated.
MeSH term(s)	Animals ; Tilapia/genetics ; Fish Diseases ; Orthomyxoviridae/genetics ; Viruses/genetics ; RNA
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2023-12-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44044-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Errors in the deposited SFTSV L protein structure.

Cusack, Stephen / Rosenthal, Maria

Nature microbiology

2021 Volume 6, Issue 5, Page(s) 549–550

MeSH term(s)	Bunyaviridae Infections ; Humans ; Phlebovirus
Language	English
Publishing date	2021-04-29
Publishing country	England
Document type	Letter ; Comment
ISSN	2058-5276
ISSN (online)	2058-5276
DOI	10.1038/s41564-021-00901-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The mechanism of genome replication and transcription in bunyaviruses.

Malet, Hélène / Williams, Harry M / Cusack, Stephen / Rosenthal, Maria

PLoS pathogens

2023 Volume 19, Issue 1, Page(s) e1011060

Abstract: Bunyaviruses are negative sense, single-strand RNA viruses that infect a wide range of vertebrate, invertebrate and plant hosts. WHO lists three bunyavirus diseases as priority diseases requiring urgent development of medical countermeasures highlighting ...

Abstract	Bunyaviruses are negative sense, single-strand RNA viruses that infect a wide range of vertebrate, invertebrate and plant hosts. WHO lists three bunyavirus diseases as priority diseases requiring urgent development of medical countermeasures highlighting their high epidemic potential. While the viral large (L) protein containing the RNA-dependent RNA polymerase is a key enzyme in the viral replication cycle and therefore a suitable drug target, our knowledge on the structure and activities of this multifunctional protein has, until recently, been very limited. However, in the last few years, facilitated by the technical advances in the field of cryogenic electron microscopy, many structures of bunyavirus L proteins have been solved. These structures significantly enhance our mechanistic understanding of bunyavirus genome replication and transcription processes and highlight differences and commonalities between the L proteins of different bunyavirus families. Here, we provide a review of our current understanding of genome replication and transcription in bunyaviruses with a focus on the viral L protein. Further, we compare within bunyaviruses and with the related influenza virus polymerase complex and highlight open questions.
MeSH term(s)	Bunyaviridae/genetics ; Bunyaviridae/metabolism ; Orthobunyavirus/genetics ; RNA ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Replication/genetics
Chemical Substances	RNA (63231-63-0) ; Viral Proteins
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011060
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Article ; Online: The host RNA polymerase II C-terminal domain is the anchor for replication of the influenza virus genome.

Krischuns, Tim / Arragain, Benoît / Isel, Catherine / Paisant, Sylvain / Budt, Matthias / Wolff, Thorsten / Cusack, Stephen / Naffakh, Nadia

Nature communications

2024 Volume 15, Issue 1, Page(s) 1064

Abstract: The current model is that the influenza virus polymerase (FluPol) binds either to host RNA polymerase II (RNAP II) or to the acidic nuclear phosphoprotein 32 (ANP32), which drives its conformation and activity towards transcription or replication of the ... ...

Abstract	The current model is that the influenza virus polymerase (FluPol) binds either to host RNA polymerase II (RNAP II) or to the acidic nuclear phosphoprotein 32 (ANP32), which drives its conformation and activity towards transcription or replication of the viral genome, respectively. Here, we provide evidence that the FluPol-RNAP II binding interface, beyond its well-acknowledged function in cap-snatching during transcription initiation, has also a pivotal role in replication of the viral genome. Using a combination of cell-based and in vitro approaches, we show that the RNAP II C-terminal-domain, jointly with ANP32, enhances FluPol replication activity. We observe successive conformational changes to switch from a transcriptase to a replicase conformation in the presence of the bound RNPAII C-terminal domain and propose a model in which the host RNAP II is the anchor for transcription and replication of the viral genome. Our data open new perspectives on the spatial coupling of viral transcription and replication and the coordinated balance between these two activities.
MeSH term(s)	RNA Polymerase II/metabolism ; RNA-Dependent RNA Polymerase/metabolism ; RNA, Viral/genetics ; Orthomyxoviridae/genetics ; DNA-Directed RNA Polymerases ; Virus Replication/genetics
Chemical Substances	RNA Polymerase II (EC 2.7.7.-) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; RNA, Viral ; DNA-Directed RNA Polymerases (EC 2.7.7.6)
Language	English
Publishing date	2024-02-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45205-2
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Article ; Online: Structure and Function of Influenza Polymerase.

Wandzik, Joanna M / Kouba, Tomas / Cusack, Stephen

Cold Spring Harbor perspectives in medicine

2021 Volume 11, Issue 9

Abstract: Influenza polymerase (FluPol) plays a key role in the viral infection cycle by transcribing and replicating the viral genome. FluPol is a multifunctional, heterotrimeric enzyme with cap-binding, endonuclease, RNA-dependent RNA polymerase and ... ...

Abstract	Influenza polymerase (FluPol) plays a key role in the viral infection cycle by transcribing and replicating the viral genome. FluPol is a multifunctional, heterotrimeric enzyme with cap-binding, endonuclease, RNA-dependent RNA polymerase and polyadenylation activities. It performs its functions in the context of the viral ribonucleoprotein particle (RNP), wherein the template viral RNA is coated by multiple copies of viral nucleoprotein. Moreover, it interacts with a number of host proteins that are essential cofactors and, consequently, adaptive mutations in the polymerase are required for crossing the avian-human species barrier. In this review, we show how mechanistic understanding of how FluPol performs its multiple functions has greatly advanced over the last decade through determination of high-resolution structures by X-ray crystallography and cryo-electron microscopy. These have revealed not only the detailed architecture of FluPol but highlighted the remarkably conformational flexibility that is inherent to its functioning as a dynamic RNA synthesis machine. Structural studies are also underpinning current attempts to develop next-generation anti-influenza drugs that directly target FluPol.
MeSH term(s)	Genome, Viral ; Humans ; Influenza, Human/genetics ; Mutation ; Nucleotides/genetics ; Protein Binding/genetics ; RNA-Dependent RNA Polymerase/genetics
Chemical Substances	Nucleotides ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a038372
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Article ; Online: Influenza Virus RNA-Dependent RNA Polymerase and the Host Transcriptional Apparatus.

Krischuns, Tim / Lukarska, Maria / Naffakh, Nadia / Cusack, Stephen

Annual review of biochemistry

2021 Volume 90, Page(s) 321–348

Abstract: Influenza virus RNA-dependent RNA polymerase (FluPol) transcribes the viral RNA genome in the infected cell nucleus. In the 1970s, researchers showed that viral transcription depends on host RNA polymerase II (RNAP II) activity and subsequently that ... ...

Abstract	Influenza virus RNA-dependent RNA polymerase (FluPol) transcribes the viral RNA genome in the infected cell nucleus. In the 1970s, researchers showed that viral transcription depends on host RNA polymerase II (RNAP II) activity and subsequently that FluPol snatches capped oligomers from nascent RNAP II transcripts to prime its own transcription. Exactly how this occurs remains elusive. Here, we review recent advances in the mechanistic understanding of FluPol transcription and early events in RNAP II transcription that are relevant to cap-snatching. We describe the known direct interactions between FluPol and the RNAP II C-terminal domain and summarize the transcription-related host factors that have been found to interact with FluPol. We also discuss open questions regarding how FluPol may be targeted to actively transcribing RNAP II and the exact context and timing of cap-snatching, which is presumed to occur after cap completion but before the cap is sequestered by the nuclear cap-binding complex.
MeSH term(s)	Host-Pathogen Interactions/physiology ; Humans ; Orthomyxoviridae/enzymology ; Orthomyxoviridae/pathogenicity ; RNA Cap-Binding Proteins/genetics ; RNA Cap-Binding Proteins/metabolism ; RNA Polymerase II/chemistry ; RNA Polymerase II/metabolism ; RNA-Dependent RNA Polymerase/genetics ; RNA-Dependent RNA Polymerase/metabolism ; Transcription, Genetic ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	RNA Cap-Binding Proteins ; Viral Proteins ; RNA Polymerase II (EC 2.7.7.-) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2021-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev-biochem-072820-100645
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Book ; Online: The mechanism of genome replication and transcription in bunyaviruses

Malet, Hélène / Williams, Harry M. / Cusack, Stephen C. / Rosenthal, Maria

2023

Abstract	Bunyaviruses are negative sense, single-strand RNA viruses that infect a wide range of vertebrate, invertebrate and plant hosts. WHO lists three bunyavirus diseases as priority diseases requiring urgent development of medical countermeasures highlighting their high epidemic potential. While the viral large (L) protein containing the RNA-dependent RNA polymerase is a key enzyme in the viral replication cycle and therefore a suitable drug target, our knowledge on the structure and activities of this multifunctional protein has, until recently, been very limited. However, in the last few years, facilitated by the technical advances in the field of cryogenic electron microscopy, many structures of bunyavirus L proteins have been solved. These structures significantly enhance our mechanistic understanding of bunyavirus genome replication and transcription processes and highlight differences and commonalities between the L proteins of different bunyavirus families. Here, we provide a review of our current understanding of genome replication and transcription in bunyaviruses with a focus on the viral L protein. Further, we compare within bunyaviruses and with the related influenza virus polymerase complex and highlight open questions. 19 1
Subject code	612
Language	English
Publishing country	de
Document type	Book ; Online
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Article ; Online: The Cap-Snatching Mechanism of Bunyaviruses.

Olschewski, Silke / Cusack, Stephen / Rosenthal, Maria

Trends in microbiology

2020 Volume 28, Issue 4, Page(s) 293–303

Abstract: In common with all segmented negative-sense RNA viruses, bunyavirus transcripts contain heterologous sequences at their 5' termini originating from capped host cell RNAs. These heterologous sequences are acquired by a so-called cap-snatching mechanism. ... ...

Abstract	In common with all segmented negative-sense RNA viruses, bunyavirus transcripts contain heterologous sequences at their 5' termini originating from capped host cell RNAs. These heterologous sequences are acquired by a so-called cap-snatching mechanism. Whereas for nuclear replicating influenza virus the source of capped primers as well as the cap-binding and endonuclease activities of the viral polymerase needed for cap snatching have been functionally and structurally well characterized, our knowledge on the expected counterparts of cytoplasmic replicating bunyaviruses is still limited and controversial. This review focuses on the cap-snatching mechanism of bunyaviruses in the light of recent structural and functional data.
MeSH term(s)	Endonucleases/chemistry ; Orthobunyavirus/genetics ; Orthobunyavirus/physiology ; Orthomyxoviridae/genetics ; RNA Caps/genetics ; RNA Caps/physiology ; RNA, Viral/genetics ; Transcription, Genetic ; Viral Proteins/metabolism ; Virus Replication
Chemical Substances	RNA Caps ; RNA, Viral ; Viral Proteins ; Endonucleases (EC 3.1.-)
Language	English
Publishing date	2020-01-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2019.12.006
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Article: The Cap-Snatching Mechanism of Bunyaviruses

Olschewski, Silke / Cusack, Stephen / Rosenthal, Maria

Trends in microbiology. 2020 Apr., v. 28, no. 4

2020

Abstract: In common with all segmented negative-sense RNA viruses, bunyavirus transcripts contain heterologous sequences at their 5′ termini originating from capped host cell RNAs. These heterologous sequences are acquired by a so-called cap-snatching mechanism. ... ...

Abstract	In common with all segmented negative-sense RNA viruses, bunyavirus transcripts contain heterologous sequences at their 5′ termini originating from capped host cell RNAs. These heterologous sequences are acquired by a so-called cap-snatching mechanism. Whereas for nuclear replicating influenza virus the source of capped primers as well as the cap-binding and endonuclease activities of the viral polymerase needed for cap snatching have been functionally and structurally well characterized, our knowledge on the expected counterparts of cytoplasmic replicating bunyaviruses is still limited and controversial. This review focuses on the cap-snatching mechanism of bunyaviruses in the light of recent structural and functional data.
Keywords	Orthobunyavirus ; Orthomyxoviridae ; messenger RNA
Language	English
Dates of publication	2020-04
Size	p. 293-303.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2019.12.006
Database	NAL-Catalogue (AGRICOLA)

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