scholarly journals TRIM22. A Multitasking Antiviral Factor

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1864
Author(s):  
Isabel Pagani ◽  
Guido Poli ◽  
Elisa Vicenzi
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Direct Interaction ◽  
Type I Interferons ◽  
Viral Gene ◽  
Target Cells ◽  
Type I ◽  
Protein Protein Interactions ◽  
Viral Genomes ◽  
Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

Engineering “Antimicrobial Peptides” and Other Peptides to Modulate Protein-Protein Interactions in Cancer

2020 ◽  
Vol 20 (32) ◽  
pp. 2970-2983
Author(s):  
Samuel J.S. Rubin ◽  
Nir Qvit
Keyword(s):  
Antimicrobial Peptides ◽  
Protein Interactions ◽  
Anticancer Agents ◽  
Cancer Therapeutics ◽  
Target Cells ◽  
Protein Protein Interactions ◽  
Peptide Backbone ◽  
Modified Peptides ◽  
Selective Death ◽  
Drug Leads

Antimicrobial peptides (AMPs) are a class of peptides found across a wide array of organisms that play key roles in host defense. AMPs induce selective death in target cells and orchestrate specific or nonspecific immune responses. Many AMPs exhibit native anticancer activity in addition to antibacterial activity, and others have been engineered as antineoplastic agents. We discuss the use of AMPs in the detection and treatment of cancer as well as mechanisms of AMP-induced cell death. We present key examples of cathelicidins and transferrins, which are major AMP families. Further, we discuss the critical roles of protein-protein interactions (PPIs) in cancer and how AMPs are well-suited to target PPIs based on their unique drug-like properties not exhibited by small molecules or antibodies. While peptides, including AMPs, can have limited stability and bioavailability, these issues can be overcome by peptide backbone modification or cyclization (e.g., stapling) and by the use of delivery systems such as cellpenetrating peptides (CPPs), respectively. We discuss approaches for optimizing drug properties of peptide and peptidomimetic leads (modified peptides), providing examples of promising techniques that may be applied to AMPs. These molecules represent an exciting resource as anticancer agents with unique therapeutic advantages that can target challenging mechanisms involving PPIs. Indeed, AMPs are suitable drug leads for further development of cancer therapeutics, and many studies to this end are underway.

scholarly journals IFITM3 and type I interferons are important for the control of influenza A virus replication in murine macrophages

Virology ◽  
2020 ◽  
Vol 540 ◽  
pp. 17-22 ◽  
Author(s):  
Sarah L. Londrigan ◽  
Linda M. Wakim ◽  
Jeffrey Smith ◽  
Anne J. Haverkate ◽  
Andrew G. Brooks ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Virus Replication ◽  
Influenza A ◽  
Type I Interferons ◽  
Type I ◽  
Murine Macrophages

IFN-κ suppresses the replication of influenza A viruses through the IFNAR-MAPK-Fos-CHD6 axis

2020 ◽  
Vol 13 (626) ◽  
pp. eaaz3381 ◽  
Author(s):  
Yongquan He ◽  
Weihui Fu ◽  
Kangli Cao ◽  
Qian He ◽  
Xiangqing Ding ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Viruses ◽  
Mitogen Activated Protein Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Influenza A Viruses ◽  
Human Lung Cells ◽  
Avian Influenza A Virus ◽  
Factor C

Type I interferons (IFNs) are the first line of defense against viral infection. Using a mouse model of influenza A virus infection, we found that IFN-κ was one of the earliest responding type I IFNs after infection with H9N2, a low-pathogenic avian influenza A virus, whereas this early induction did not occur upon infection with the epidemic-causing H7N9 virus. IFN-κ efficiently suppressed the replication of various influenza viruses in cultured human lung cells, and chromodomain helicase DNA binding protein 6 (CHD6) was the major effector for the antiviral activity of IFN-κ, but not for that of IFN-α or IFN-β. The induction of CHD6 required both of the type I IFN receptor subunits IFNAR1 and IFNAR2, the mitogen-activated protein kinase (MAPK) p38, and the transcription factor c-Fos but was independent of signal transducer and activator of transcription 1 (STAT1) activity. In addition, we showed that pretreatment with IFN-κ protected mice from lethal influenza viral challenge. Together, our findings identify an IFN-κ–specific pathway that constrains influenza A virus and provide evidence that IFN-κ may have potential as a preventative and therapeutic agent against influenza A virus.

Differential expression and activity of the porcine type I interferon family

2010 ◽  
Vol 42 (2) ◽  
pp. 248-258 ◽  
Author(s):  
Yongming Sang ◽  
Raymond R. R. Rowland ◽  
Richard A. Hesse ◽  
Frank Blecha
Keyword(s):  
Antiviral Activity ◽  
Expression Profiles ◽  
Type I Interferons ◽  
Respiratory Syndrome Virus ◽  
Target Cells ◽  
Type I ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Antiviral Activities ◽  
Vesicular Stomatitis

Type I interferons (IFNs) are central to innate and adaptive immunity, and many have unique developmental and physiological functions. However, in most species, only two subtypes, IFN-α and IFN-β, have been well studied. Because of the increasing importance of zoonotic viral diseases and the use of pigs to address human research questions, it is important to know the complete repertoire and activity of porcine type I IFNs. Here we show that porcine type I IFNs comprise at least 39 functional genes distributed along draft genomic sequences of chromosomes 1 and 10. These functional IFN genes are classified into 17 IFN-α subtypes, 11 IFN-δ subtypes, 7 IFN-ω subtypes, and single-subtype subclasses of IFN-αω, IFN-β, IFN-ε, and IFN-κ. We found that porcine type I IFNs have diverse expression profiles and antiviral activities against porcine reproductive and respiratory syndrome virus (PRRSV) and vesicular stomatitis virus (VSV), with activity ranging from 0 to >105 U·ng−1·ml−1. Whereas most IFN-α subtypes retained the greatest antiviral activity against both PRRSV and VSV in porcine and MARC-145 cells, some IFN-δ and IFN-ω subtypes, IFN-β, and IFN-αω differed in their antiviral activity based on target cells and viruses. Several IFNs, including IFN-α7/11, IFN-δ2/7, and IFN-ω4, exhibited minimal or no antiviral activity in the tested target cell-virus systems. Thus comparative studies showed that antiviral activity of porcine type I IFNs is virus- and cell-dependent, and IFN-αs are positively correlated with induction of MxA, an IFN-stimulated gene. Collectively, these data provide fundamental genomic information for porcine type I IFNs, information that is necessary for understanding porcine physiological and antiviral responses.

An activity-based probe reveals dynamic protein–protein interactions mediating IGF-1R transactivation by the GABAB receptor

2012 ◽  
Vol 443 (3) ◽  
pp. 627-634 ◽  
Author(s):  
Xin Lin ◽  
Xin Li ◽  
Ming Jiang ◽  
Linhai Chen ◽  
Chanjuan Xu ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Complex ◽  
Tyrosine Kinases ◽  
Chemical Biology ◽  
Molecular Mechanisms ◽  
Gabab Receptor ◽  
Type I ◽  
Protein Protein Interactions ◽  
Downstream Effectors ◽  
Factor Type

Many GPCRs (G-protein-coupled receptors) can activate RTKs (receptor tyrosine kinases) in the absence of RTK ligands, a phenomenon called transactivation. However, the underlying molecular mechanisms remain undefined. In the present study we investigate the molecular basis of GABAB (γ-aminobutyric acid B) receptor-mediated transactivation of IGF-1R (insulin-like growth factor type I receptor) in primary neurons. We take a chemical biology approach by developing an activity-based probe targeting the GABAB receptor. This probe enables us first to lock the GABAB receptor in an inactive state and then activate it with a positive allosteric modulator, thereby permitting monitoring of the dynamic of the protein complex associated with IGF-1R transactivation. We find that activation of the GABAB receptor induces a dynamic assembly and disassembly of a protein complex, including both receptors and their downstream effectors. FAK (focal adhesion kinase), a non-RTK, plays a key role in co-ordinating this dynamic process. Importantly, this dynamic of the GABAB receptor-associated complex is critical for transactivation and transactivation-dependent neuronal survival. The present study has identified an important mechanism underlying GPCR transactivation of RTKs, which was enabled by a new chemical biology tool generally applicable for dissecting GPCR signalling.

scholarly journals The Autoregulatory and Transactivating Functions of the Human Cytomegalovirus IE86 Protein Use Independent Mechanisms for Promoter Binding

2007 ◽  
Vol 81 (11) ◽  
pp. 5807-5818 ◽  
Author(s):  
Dustin T. Petrik ◽  
Kimberly P. Schmitt ◽  
Mark F. Stinski
Keyword(s):  
Human Cytomegalovirus ◽  
Protein Interactions ◽  
Chromatin Immunoprecipitation ◽  
Viral Gene Expression ◽  
Artificial Chromosome ◽  
Viral Gene ◽  
Chip Assay ◽  
Protein Protein Interactions ◽  
Multiple Sequence ◽  
Viral Genes

ABSTRACT The functions of the human cytomegalovirus (HCMV) IE86 protein are paradoxical, as it can both activate and repress viral gene expression through interaction with the promoter region. Although the mechanism for these functions is not clearly defined, it appears that a combination of direct DNA binding and protein-protein interactions is involved. Multiple sequence alignment of several HCMV IE86 homologs reveals that the amino acids 534LPIYE538 are conserved between all primate and nonprimate CMVs. In the context of a bacterial artificial chromosome (BAC), mutation of both P535 and Y537 to alanines (P535A/Y537A) results in a nonviable BAC. The defective HCMV BAC does not undergo DNA replication, although the P535A/Y537A mutant IE86 protein appears to be stably expressed. The P535A/Y537A mutant IE86 protein is able to negatively autoregulate transcription from the major immediate-early (MIE) promoter and was recruited to the MIE promoter in a chromatin immunoprecipitation (ChIP) assay. However, the P535A/Y537A mutant IE86 protein was unable to transactivate early viral genes and was not recruited to the early viral UL4 and UL112 promoters in a ChIP assay. From these data, we conclude that the transactivation and repressive functions of the HCMV IE86 protein can be separated and must occur through independent mechanisms.

scholarly journals Role of Toll-like Receptors in Adjuvant-Augmented Immune Therapies

2006 ◽  
Vol 3 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Tsukasa Seya ◽  
Takashi Akazawa ◽  
Tadayuki Tsujita ◽  
Misako Matsumoto
Keyword(s):  
Type I Interferons ◽  
Target Cells ◽  
Type I ◽  
Toll Like Receptors ◽  
Myeloid Dendritic Cells ◽  
Therapeutic Vaccines ◽  
Adjuvant Activity ◽  
Host Immune Responses

Effective therapeutic vaccines contain two primary constituents, antigen and adjuvant. Adjuvants consisting of microbial pattern molecules play a central role in vaccination. Successful vaccine requires efficient induction of antibody (Ab), type I interferons (IFN), cytokines/chemokines, cytotoxic T lymphocytes (CTL) and/or NK cells. Toll-like receptors (TLRs) in myeloid dendritic cells (mDC) essentially act as adjuvant receptors and sustain the molecular basis of adjuvant activity. Current consensus is that TLRs and their adapters introduce signals to preferentially induce IFN-α/β, chemokines and proinflammatory cytokines, and mature mDC to augment antigen presentation. Although most of these data were obtained with mice, the results are presumed to be adaptable to humans. Whenever TLR pathway is activated in mDC, NK and/or CTL activation is promoted. For induction of antigen-specific CTL toward phagocytosed material, cross-priming must be induced in mDC, which is also sustained by TLR signaling in mDC. Since the TLR responses vary with different adjuvants, mDC functions are skewed depending on adjuvant-specific direction of mDC maturation. It appears that the directed maturation of mDC largely relies on selection of appropriate sets of TLRs and their adapter signaling pathways. Synthetic chimera molecules consisting of TLR agonists and target antigens are found to be effective in induction of CTL to eliminate target cellsin vivo. Here, we review the role of human TLRs and adapters in a variety of host immune responses. We will also describe the relevance of adjuvants in the manipulation of receptors and adapters in vaccine therapy.

scholarly journals Phosphorylation modulates liquid-liquid phase separation of the SARS-CoV-2 N protein

2020 ◽  
Author(s):  
Christopher R. Carlson ◽  
Jonathan B. Asfaha ◽  
Chloe M. Ghent ◽  
Conor J. Howard ◽  
Nairi Hartooni ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Viral Genome ◽  
Rna Binding ◽  
Viral Gene ◽  
Protein Protein Interactions ◽  
N Protein ◽  
Binding Domains ◽  
Genome Transcription ◽  
Liquid Liquid Phase Separation

The nucleocapsid (N) protein of coronaviruses serves two major functions: compaction of the RNA genome in the virion and regulation of viral gene transcription in the infected cell1–3. The N protein contains two globular RNA-binding domains surrounded by regions of intrinsic disorder4. Phosphorylation of the central disordered region is required for normal viral genome transcription5,6, which occurs in a cytoplasmic structure called the replication transcription complex (RTC)7–11. It is not known how phosphorylation controls N protein function. Here we show that the N protein of SARS-CoV-2, together with viral RNA, forms biomolecular condensates12–15. Unmodified N protein forms partially ordered gel-like structures that depend on multivalent RNA-protein and protein-protein interactions. Phosphorylation reduces a subset of these interactions, generating a more liquid-like droplet. We speculate that distinct oligomeric states support the two functions of the N protein: unmodified protein forms a structured oligomer that is suited for nucleocapsid assembly, and phosphorylated protein forms a liquid-like compartment for viral genome processing. Inhibitors of N protein phosphorylation could therefore serve as antiviral therapy.

scholarly journals Where does axon guidance lead us?

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 78 ◽  
Author(s):  
Esther Stoeckli
Keyword(s):  
Axon Guidance ◽  
Protein Interactions ◽  
Neural Circuit ◽  
Surface Expression ◽  
Target Cells ◽  
Protein Protein Interactions ◽  
Guidance Receptors ◽  
Recent Developments ◽  
Genomic Studies ◽  
Circuit Formation

During neural circuit formation, axons need to navigate to their target cells in a complex, constantly changing environment. Although we most likely have identified most axon guidance cues and their receptors, we still cannot explain the molecular background of pathfinding for any subpopulation of axons. We lack mechanistic insight into the regulation of interactions between guidance receptors and their ligands. Recent developments in the field of axon guidance suggest that the regulation of surface expression of guidance receptors comprises transcriptional, translational, and post-translational mechanisms, such as trafficking of vesicles with specific cargos, protein-protein interactions, and specific proteolysis of guidance receptors. Not only axon guidance molecules but also the regulatory mechanisms that control their spatial and temporal expression are involved in synaptogenesis and synaptic plasticity. Therefore, it is not surprising that genes associated with axon guidance are frequently found in genetic and genomic studies of neurodevelopmental disorders.

scholarly journals Dynamic rewiring of the human interactome by interferon signalling

2019 ◽  
Author(s):  
Craig H. Kerr ◽  
Michael A. Skinnider ◽  
Angel M. Madero ◽  
Daniel D.T. Andrews ◽  
R. Greg Stacey ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Interaction Network ◽  
Cell Types ◽  
Antiviral Response ◽  
Type I ◽  
Protein Protein Interactions ◽  
Human Interactome ◽  
Viral Pathogens ◽  
Protein Protein Interaction ◽  
Dependent Protein

ABSTRACTBackgroundThe type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). Transcriptomic and biochemical approaches have established comprehensive catalogues of ISGs across species and cell types, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to delineate the effects of IFN signalling on the human proteome, culminating in the use of protein correlation profiling to map IFN-induced rearrangements in the human protein-protein interaction network.ResultsWe identified >27,000 protein interactions in IFN-stimulated and unstimulated cells, many of which involve proteins associated with human disease and are observed exclusively within the IFN-stimulated network. Differential network analysis reveals interaction rewiring across a surprisingly broad spectrum of cellular pathways in the antiviral response. We identify IFN-dependent protein-protein interactions mediating novel regulatory mechanisms at the transcriptional and translational levels, with one such interaction modulating the transcriptional activity of STAT1. Moreover, we reveal IFN-dependent changes in ribosomal composition that act to buffer ISG protein synthesis.ConclusionsOur map of the IFN interactome provides a global view of the complex cellular networks activated during the antiviral response, placing ISGs in a functional context, and serves as a framework to understand how these networks are dysregulated in autoimmune or inflammatory disease.

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