The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription

Brandt, Janine; Wendt, Lisa; Bodmer, Bianca S.; Mettenleiter, Thomas C.; Hoenen, Thomas

doi:10.3390/cells9051126

Cited by 23 publications

(18 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The phosphorylated mitogen-activated protein kinase p38, a key regulator of cellular inflammatory and stress responses, and the O-linked N -acetylglucosamine (OGN) transferase, an enzyme that catalyzes the posttranslational addition of OGN to protein and is also involved in stress response, are sequestered in RSV IBs [ 99 ]. Finally, EBOV NP recruits several proteins into the IBs, which include the nuclear RNA export factor NFX1 to drive viral protein synthesis [ 100 ] and the histone-lysine-methyltransferase SMYD3 [ 101 ] as well as the CAD protein [ 102 ] to facilitate mRNA transcription and replication.…”

Section: Interaction Of Viral Liquid Ibs With Host-cell Machineriesmentioning

confidence: 99%

Negri bodies and other virus membrane-less replication compartments

Nevers

Albertini

Lagaudrière-Gesbert

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

Viruses reshape the organization of the cell interior to achieve different steps of their cellular cycle. Particularly, viral replication and assembly often take place in viral factories where specific viral and cellular proteins as well as nucleic acids concentrate. Viral factories can be either membrane-delimited or devoid of any cellular membranes. In the latter case, they are referred as membrane-less replication compartments. The most emblematic ones are the Negri bodies, which are inclusion bodies that constitute the hallmark of rabies virus infection. Interestingly, Negri bodies and several other viral replication compartments have been shown to arise from a liquid-liquid phase separation process and, thus, constitute a new class of liquid organelles. This is a paradigm shift in the field of virus replication. Here, we review the different aspects of membrane-less virus replication compartments with a focus on the Mononegavirales order and discuss their interactions with the host cell machineries and the cytoskeleton. We particularly examine the interplay between viral factories and the cellular innate immune response, of which several components also form membrane-less condensates in infected cells.

show abstract

Section: Interaction Of Viral Liquid Ibs With Host-cell Machineriesmentioning

confidence: 99%

Negri bodies and other virus membrane-less replication compartments

Nevers

Albertini

Lagaudrière-Gesbert

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

show abstract

“…Different groups reported an intriguing punctuated patterns of CAD in the cytoplasm that does not correlate with mitochondria, cytoskeleton, lysosomes or other subcellular structures. 14 , 50 , 62 , 67 , 68 , 69 Remarkably, this dotted distribution is enhanced upon activation of de novo pyrimidine synthesis. In addition to MAPK and PKA phosphorylation, CAD is phosphorylated at the DHO‐ATC linker by the S6 kinase in the downstream pathway of mTORC1.…”

Section: Localization Of Cad In the Cellmentioning

confidence: 96%

“…But the location of CAD is not an ended question. Different groups reported an intriguing punctuated patterns of CAD in the cytoplasm that does not correlate with mitochondria, cytoskeleton, lysosomes or other subcellular structures 14,50,62,67–69 . Remarkably, this dotted distribution is enhanced upon activation of de novo pyrimidine synthesis.…”

Section: Localization Of Cad In the Cellmentioning

confidence: 98%

Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease

Caño-Ochoa

Ramón‐Maiques

2021

Protein Science

View full text Add to dashboard Cite

CAD is a 1.5 MDa particle formed by hexameric association of a 250 kDa protein divided into different enzymatic domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutaminasedependent Carbamoyl phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase. The pathway for de novo pyrimidine synthesis is essential for cell proliferation and is conserved in all living organisms, but the covalent linkage of the first enzymatic activities into a multienzymatic CAD particle is unique to animals. In other organisms, these enzymatic activities are encoded as monofunctional proteins for which there is abundant structural and biochemical information. However, the knowledge about CAD is scarce and fragmented. Understanding CAD requires not only to determine the threedimensional structures and define the catalytic and regulatory mechanisms of the different enzymatic domains, but also to comprehend how these domains entangle and work in a coordinated and regulated manner. This review summarizes significant progress over the past 10 years toward the characterization of CAD's architecture, function, regulatory mechanisms, and cellular compartmentalization, as well as the recent finding of a new and rare neurometabolic disorder caused by defects in CAD activities. K E Y W O R D Saspartate transcarbamoylase, carbamoyl phosphate synthetase, de novo pyrimidine biosynthesis, dihydroorotase, multienzymatic protein, nucleotide metabolism, rare diseases | INTRODUCTIONPyrimidine nucleotides are building blocks of DNA and RNA and key activators of intermediate metabolites in a number of cellular processes, including glycosylation and carbohydrate and phospholipid synthesis. 1,2 The cells obtain the supply of pyrimidines through two different metabolic pathways (Figure 1). Slowly dividing or differentiated cells use preferentially salvage pathways to uptake preformed nucleosides (e.g., uridine) from the diet or from the breakdown of nucleic acids, whereas, proliferating cells, whether normal (e.g., activated lymphocytes) or tumoral, depend on de novo ("of new") synthesis of pyrimidine nucleotides. The de novo pathway consists of six enzymatic steps yielding uridine 5-monophosphate (UMP), from which all other pyrimidine nucleotides are made (Figure 1). 3 In a first step, carbamoyl phosphate synthetase (CPS; EC 6.3.5.5) makes

show abstract

“…Which and how host cell factors contribute to filovirus IB formation is not known. Several cellular proteins, like Tsg101, IQ-GAP1, NXF1, CAD and SRPK1, and others have been identified inside IBs, being important for different steps of the filovirus replication cycle [172,177,[184][185][186][187]. Interestingly, it was published recently that ER contact sites regulate the dynamics of membrane-less organelles like P-bodies [188].…”

Section: Filoviridae: Ibs Of Marv and Ebovmentioning

confidence: 99%

New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections

Dolnik

Gerresheim

Biedenkopf

2021

Cells

View full text Add to dashboard Cite

Infections by negative strand RNA viruses (NSVs) induce the formation of viral inclusion bodies (IBs) in the host cell that segregate viral as well as cellular proteins to enable efficient viral replication. The induction of those membrane-less viral compartments leads inevitably to structural remodeling of the cellular architecture. Recent studies suggested that viral IBs have properties of biomolecular condensates (or liquid organelles), as have previously been shown for other membrane-less cellular compartments like stress granules or P-bodies. Biomolecular condensates are highly dynamic structures formed by liquid-liquid phase separation (LLPS). Key drivers for LLPS in cells are multivalent protein:protein and protein:RNA interactions leading to specialized areas in the cell that recruit molecules with similar properties, while other non-similar molecules are excluded. These typical features of cellular biomolecular condensates are also a common characteristic in the biogenesis of viral inclusion bodies. Viral IBs are predominantly induced by the expression of the viral nucleoprotein (N, NP) and phosphoprotein (P); both are characterized by a special protein architecture containing multiple disordered regions and RNA-binding domains that contribute to different protein functions. P keeps N soluble after expression to allow a concerted binding of N to the viral RNA. This results in the encapsidation of the viral genome by N, while P acts additionally as a cofactor for the viral polymerase, enabling viral transcription and replication. Here, we will review the formation and function of those viral inclusion bodies upon infection with NSVs with respect to their nature as biomolecular condensates.

show abstract

The Cellular Protein CAD is Recruited into Ebola Virus Inclusion Bodies by the Nucleoprotein NP to Facilitate Genome Replication and Transcription

Cited by 23 publications

References 46 publications

Negri bodies and other virus membrane-less replication compartments

Negri bodies and other virus membrane-less replication compartments

Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease

New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections

Contact Info

Product

Resources

About