HSV-1 ICP27
from Rozanne M. Sandri-Goldin writing in Alphaherpesviruses: Molecular Virology:
Herpes simplex virus 1 (HSV-1) protein ICP27 is a multifunctional regulator that is essential for HSV-1 infection. ICP27 performs a number of different functions during infection that include inhibiting cellular pre-mRNA splicing, stimulating viral early and late gene transcription by recruiting cellular RNA polymerase II to viral replication sites, binding and exporting viral RNA to the cytoplasm and stimulating translation of some HSV-1 transcripts by binding translation initiation factors. ICP27 also recruits Hsc70 to nuclear foci (VICE domains) that are enriched in chaperones and components of the proteasome, and which are believed to be involved in nuclear protein quality control. ICP27 interacts with a number of proteins and it binds RNA. Post-translational modifications have been demonstrated to regulate ICP27's interactions with several proteins. NMR analysis of the N-terminus showed that it is highly flexible, which may be necessary for switching between different protein interactions. Further, ICP27 undergoes a head-to-tail intramolecular association that may also regulate its interactions, especially with proteins that require that both the N- and C-termini of ICP27 be intact for interaction. A recent review covers the different activities of ICP27 and what we know about how these activities are regulated.
Further reading: Alphaherpesviruses: Molecular Virology
Herpes simplex virus 1 (HSV-1) protein ICP27 is a multifunctional regulator that is essential for HSV-1 infection. ICP27 performs a number of different functions during infection that include inhibiting cellular pre-mRNA splicing, stimulating viral early and late gene transcription by recruiting cellular RNA polymerase II to viral replication sites, binding and exporting viral RNA to the cytoplasm and stimulating translation of some HSV-1 transcripts by binding translation initiation factors. ICP27 also recruits Hsc70 to nuclear foci (VICE domains) that are enriched in chaperones and components of the proteasome, and which are believed to be involved in nuclear protein quality control. ICP27 interacts with a number of proteins and it binds RNA. Post-translational modifications have been demonstrated to regulate ICP27's interactions with several proteins. NMR analysis of the N-terminus showed that it is highly flexible, which may be necessary for switching between different protein interactions. Further, ICP27 undergoes a head-to-tail intramolecular association that may also regulate its interactions, especially with proteins that require that both the N- and C-termini of ICP27 be intact for interaction. A recent review covers the different activities of ICP27 and what we know about how these activities are regulated.
Further reading: Alphaherpesviruses: Molecular Virology
Translational Control in Herpes Simplex Virus-infected Cells
from Ian Mohr writing in Alphaherpesviruses: Molecular Virology:
Like all viruses, alpha-herpesviruses are completely reliant upon the protein synthesis machinery resident in their host cells. In particular, viral mRNAs must effectively compete with cellular mRNAs to engage ribosomes. To ensure high-level production of the polypeptides required for their lytic replication, multiple independent gene products expressed by the model α-herpesvirus HSV-1 effectively seize control of critical host cell translational control pathways. Surprisingly, while host protein synthesis is profoundly suppressed by global changes in mRNA metabolism, the assembly of a multi-subunit, cap-binding translation initiation factor complex required to recruit 40S subunits to mRNA is directly stimulated. This involves both inactivation of a cellular translational repressor by viral functions, and direct interaction between specific viral proteins and select cellular translation initiation factors. In addition to their dependence on cellular components required for mRNA translation, virus-encoded functions must preserve its activity by neutralizing potent host responses capable of incapacitating the translation machinery, one of which senses stress within the endoplasmic reticulum lumen and another of which functions as a host innate defense component by sensing double-stranded RNA, a molecular signature of viral infection. A recent review discusses in detail the many virus-host interactions that are presently known to control translation in cells productively infected with HSV-1 and highlights recent developments in this area.
Further reading: Alphaherpesviruses: Molecular Virology
Like all viruses, alpha-herpesviruses are completely reliant upon the protein synthesis machinery resident in their host cells. In particular, viral mRNAs must effectively compete with cellular mRNAs to engage ribosomes. To ensure high-level production of the polypeptides required for their lytic replication, multiple independent gene products expressed by the model α-herpesvirus HSV-1 effectively seize control of critical host cell translational control pathways. Surprisingly, while host protein synthesis is profoundly suppressed by global changes in mRNA metabolism, the assembly of a multi-subunit, cap-binding translation initiation factor complex required to recruit 40S subunits to mRNA is directly stimulated. This involves both inactivation of a cellular translational repressor by viral functions, and direct interaction between specific viral proteins and select cellular translation initiation factors. In addition to their dependence on cellular components required for mRNA translation, virus-encoded functions must preserve its activity by neutralizing potent host responses capable of incapacitating the translation machinery, one of which senses stress within the endoplasmic reticulum lumen and another of which functions as a host innate defense component by sensing double-stranded RNA, a molecular signature of viral infection. A recent review discusses in detail the many virus-host interactions that are presently known to control translation in cells productively infected with HSV-1 and highlights recent developments in this area.
Further reading: Alphaherpesviruses: Molecular Virology
Herpes Simplex Virus Regulatory Protein ICP4
ICP4 is expressed from the HSV genome very early in infection. It is a large structurally complex nuclear phosphoprotein that is essential for viral growth largely due to its requirement for the transcriptional activation of most HSV early and late genes. It also acts a repressor of transcription under certain circumstances. The HSV genome is transcribed by RNA polII, and ICP4 interacts with components of the RNA polII transcription machinery to carry out is functions in transcription. The interactions that are important for its functions can be genetically defined implicating a modular composition of the ICP4 protein. ICP4 also plays a specific role in virus growth in sympathetic neurons implicating a specific function in pathogenesis. A recent review describes what is known about ICP4 from many genetic, biological and biochemical studies, from many laboratories.
Further reading: Alphaherpesviruses: Molecular Virology
Further reading: Alphaherpesviruses: Molecular Virology
Varicella Zoster Virus Transcriptional Regulation
Varicella-zoster virus (VZV) encodes three immediate-early proteins, IE4, IE62, and IE63; however, only IE62 has TAATGARAT-like sequences in its promoter which are present in the promoters of each of the herpes simplex virus immediate-early proteins. The TAATGARAT-like elements on the IE62 promoter bind to VZV ORF10 protein, Oct, and HCF-1. In addition, histone methyltransferases are recruited to the IE62 promoter to modify chromatin to a transcriptionally active form. VZV IE62, the major VZV transactivator binds to VZV IE4 and IE63, and Med25, part of the mediator complex which upregulates gene expression. VZV IE62, IE4, and IE63 are present in the viral tegument where they may help to regulate transcription early in infection. IE63 binds to several cellular proteins including ASF1 and RNA polymerase II. Two hypotheses have been proposed for regulation of VZV gene expression during latency. First, relocalization of HCF-1 from the cytoplasm to the nucleus of sensory ganglia in response to stimuli associated with reactivation may help to augment transcription of IE62 to reactivate VZV from latency. Second, promoters of latent genes are maintained in a euchromatic state allowing their transcription, while promoters of genes not associated with latency are in a heterochromatic state resulting in repression of transcription.
Further reading: Alphaherpesviruses: Molecular Virology
Further reading: Alphaherpesviruses: Molecular Virology
MicroRNAs as Regulators of Host-virus Interactions
from Sassan Asgari and Christopher S. Sullivan in Insect Virology
MicroRNAs (miRNAs) are small non-coding RNA molecules that play a central role in the regulation of gene expression impacting many biological processes. These include development, cancer, apoptosis, immunity, and longevity. In addition, accumulating evidence suggest that miRNAs are likely to be involved in host-virus interactions by modulating expression levels of either defence genes or virus genes. Several groups of animal viruses, as well as insect viruses, encode miRNAs that are instrumental in virus biology, including replication, pathogenesis and latency. Of interest is the biogenesis of miRNAs, current approaches to the discovery of miRNAs, their mode of action and strategies for determining viral miRNA function.
Further reading: Insect Virology
MicroRNAs (miRNAs) are small non-coding RNA molecules that play a central role in the regulation of gene expression impacting many biological processes. These include development, cancer, apoptosis, immunity, and longevity. In addition, accumulating evidence suggest that miRNAs are likely to be involved in host-virus interactions by modulating expression levels of either defence genes or virus genes. Several groups of animal viruses, as well as insect viruses, encode miRNAs that are instrumental in virus biology, including replication, pathogenesis and latency. Of interest is the biogenesis of miRNAs, current approaches to the discovery of miRNAs, their mode of action and strategies for determining viral miRNA function.
Further reading: Insect Virology
Thiol-based sensory factors
from Haike Antelmann and Peter Zuber in Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
Bacteria regularly encounter Reactive Oxygen, Nitrogen and Electrophilic Species (ROS, RNS, RES) that are generated inside the cells by incomplete reduction of molecular oxygen, imbalanced metabolic processes or applied externally by toxic or antimicrobial compounds. The response to such reactive agents is mediated by redox-sensitive transcription factors that exploit the unique chemistry of cysteine thiol groups. Redox-sensitive regulatory proteins bear cysteine residues that can undergo post-translational modification, leading to either activation or inactivation of the transcription factors. This in turn results in responses that are aimed to detoxify the reactive species or alleviate the damage they cause. Different thiol-modifications are implicated in redox-sensing depending on the number of redox-active Cys residues and their reactivity, the oxidant to which they react, and the prevailing in vitro or in vivo conditions. Redox-sensitive proteins with more than one reactive Cys residue undergo in most cases reversible inter- and/or intramolecular disulfide linkages, which serve as sensing mechanisms for OxyR, the 2-Cys OhrR family, MexR, OspR, Spx, CprK and CrtJ. In contrast to these classical thiol-disulfide-switches, transcription factors with one redox-active Cys residue are reversibly regulated via initial sulphenic acid formation, S-thiolation with low molecular weight (LMW) thiols and sulfenamide formation with the backbone amide as shown for OxyR, the 1-Cys OhrR ortholog, MgrA and SarZ. However, the thiol group of the 1-Cys OhrR protein can also be irreversibly modified by overoxidation to sulfinic and sulfonic acids in response to strong oxidants. RES such as quinones were shown to modify the YodB repressor irreversibly by thiol-(S)-alkylation. In addition to redox-sensing transcription factors, LMW thiols and the thioredoxin/thioredoxin reductase system maintain the thiol-redox-balance of the cell upon exposure to reactive species. Here we review (1) enzymatic redox control mechanisms by thiol-disulfide reductases and (2) the current knowledge of bacterial redox-sensitive transcription factors that function without metal cofactors, including OxyR, OhrR, MexR, OspR, MgrA, SarZ, YodB, Spx, CprK and PspR/CrtJ. Each of these transcription factors senses unique signals including ROS, RNS, RES, antibiotic and haloorganic compounds, or the cellular oxygen level and light that are transduced via diverse redox-sensing mechanisms involving different reversible and irreversible thiol-modifications.
Further reading: Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
Bacteria regularly encounter Reactive Oxygen, Nitrogen and Electrophilic Species (ROS, RNS, RES) that are generated inside the cells by incomplete reduction of molecular oxygen, imbalanced metabolic processes or applied externally by toxic or antimicrobial compounds. The response to such reactive agents is mediated by redox-sensitive transcription factors that exploit the unique chemistry of cysteine thiol groups. Redox-sensitive regulatory proteins bear cysteine residues that can undergo post-translational modification, leading to either activation or inactivation of the transcription factors. This in turn results in responses that are aimed to detoxify the reactive species or alleviate the damage they cause. Different thiol-modifications are implicated in redox-sensing depending on the number of redox-active Cys residues and their reactivity, the oxidant to which they react, and the prevailing in vitro or in vivo conditions. Redox-sensitive proteins with more than one reactive Cys residue undergo in most cases reversible inter- and/or intramolecular disulfide linkages, which serve as sensing mechanisms for OxyR, the 2-Cys OhrR family, MexR, OspR, Spx, CprK and CrtJ. In contrast to these classical thiol-disulfide-switches, transcription factors with one redox-active Cys residue are reversibly regulated via initial sulphenic acid formation, S-thiolation with low molecular weight (LMW) thiols and sulfenamide formation with the backbone amide as shown for OxyR, the 1-Cys OhrR ortholog, MgrA and SarZ. However, the thiol group of the 1-Cys OhrR protein can also be irreversibly modified by overoxidation to sulfinic and sulfonic acids in response to strong oxidants. RES such as quinones were shown to modify the YodB repressor irreversibly by thiol-(S)-alkylation. In addition to redox-sensing transcription factors, LMW thiols and the thioredoxin/thioredoxin reductase system maintain the thiol-redox-balance of the cell upon exposure to reactive species. Here we review (1) enzymatic redox control mechanisms by thiol-disulfide reductases and (2) the current knowledge of bacterial redox-sensitive transcription factors that function without metal cofactors, including OxyR, OhrR, MexR, OspR, MgrA, SarZ, YodB, Spx, CprK and PspR/CrtJ. Each of these transcription factors senses unique signals including ROS, RNS, RES, antibiotic and haloorganic compounds, or the cellular oxygen level and light that are transduced via diverse redox-sensing mechanisms involving different reversible and irreversible thiol-modifications.
Further reading: Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
Sensory Mechanisms in Bacteria
from Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
Bacteria have evolved extraordinary abilities to detect physical and chemical signals, both within their own cells and in the extracellular environment. The interaction of a signal with its receptor (usually a protein or RNA molecule) triggers a series of events that lead to reprogramming of cellular physiology, typically as a consequence of altered patterns of gene expression. In this way, the bacterial cell is able to mount appropriate and effective responses to changing physical and/or chemical environments. The versatility with which many bacteria adapt to environmental change underlies many important aspects of microbiology. For example, pathogens encounter multiple environments as they invade a host from the outside, and then progress through different sites within host tissues. There is growing evidence that pathogenic bacteria make use of physical and chemical cues to signal their presence in a suitable host, and need to adapt to the host environment in order to mount a successful infection. On the other hand, it should not be assumed that all signals to which bacteria must respond originate in the extracellular environment. For many species, even the cosseted life in a laboratory shake flask is 'stressful', in the sense that there is often a need to avoid or reverse the effects of harmful intermediates or by-products of metabolism. For example, all organisms that use dioxygen as a terminal electron acceptor have to deal with the reactive oxygen species that arise as adventitious by-products of aerobic metabolism. In bacteria, multiple protein receptors for oxygen radicals have been described, which control the expression of genes encoding enzymes that detoxify oxygen radicals or repair the damage that they cause.
Further reading: Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
Bacteria have evolved extraordinary abilities to detect physical and chemical signals, both within their own cells and in the extracellular environment. The interaction of a signal with its receptor (usually a protein or RNA molecule) triggers a series of events that lead to reprogramming of cellular physiology, typically as a consequence of altered patterns of gene expression. In this way, the bacterial cell is able to mount appropriate and effective responses to changing physical and/or chemical environments. The versatility with which many bacteria adapt to environmental change underlies many important aspects of microbiology. For example, pathogens encounter multiple environments as they invade a host from the outside, and then progress through different sites within host tissues. There is growing evidence that pathogenic bacteria make use of physical and chemical cues to signal their presence in a suitable host, and need to adapt to the host environment in order to mount a successful infection. On the other hand, it should not be assumed that all signals to which bacteria must respond originate in the extracellular environment. For many species, even the cosseted life in a laboratory shake flask is 'stressful', in the sense that there is often a need to avoid or reverse the effects of harmful intermediates or by-products of metabolism. For example, all organisms that use dioxygen as a terminal electron acceptor have to deal with the reactive oxygen species that arise as adventitious by-products of aerobic metabolism. In bacteria, multiple protein receptors for oxygen radicals have been described, which control the expression of genes encoding enzymes that detoxify oxygen radicals or repair the damage that they cause.
Further reading: Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
Signal Recognition Book
Stephen Spiro and Ray Dixon (Texas, USA and Norwich,UK; respectively) present a new publication Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition
This book reviews a selection of important model systems, providing a timely snapshot of the current state of research in the field. The book opens with an introductory chapter that reviews the diversity of signal recognition mechanisms, illustrating the breadth of the field. Subsequent chapters include descriptions of the sensing of ligands (alpha-ketoglutarate, adenylate energy charge, glutamine and xenobiotic compounds), chemoreceptors, iron-sulfur cluster-based sensors, metal-dependent and metal-responsive sensors, thiol-based sensors, and PDZ domains as sensors of other proteins read more ....
This book reviews a selection of important model systems, providing a timely snapshot of the current state of research in the field. The book opens with an introductory chapter that reviews the diversity of signal recognition mechanisms, illustrating the breadth of the field. Subsequent chapters include descriptions of the sensing of ligands (alpha-ketoglutarate, adenylate energy charge, glutamine and xenobiotic compounds), chemoreceptors, iron-sulfur cluster-based sensors, metal-dependent and metal-responsive sensors, thiol-based sensors, and PDZ domains as sensors of other proteins read more ....
 | Edited by: Stephen Spiro and Ray Dixon ISBN: 978-1-904455-69-1 Publisher: Caister Academic Press Publication Date: September 2010 Cover: Hardback |