Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Signal Transduct Target Ther ; 8(1): 1, 2023 01 02.
Article in English | MEDLINE | ID: covidwho-2244040

ABSTRACT

Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.


Subject(s)
Cell Communication , Integrins , Integrins/genetics , Cell Adhesion , Signal Transduction , Peptides
2.
Nucleic Acids Res ; 50(D1): D497-D508, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-2232151

ABSTRACT

Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for the study of motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository of manually curated, experimentally validated short linear motifs (SLiMs). An increasing number of SLiM-mediated interactions are discovered each year and keeping the resource up-to-date continues to be a great challenge. In the current update, 30 novel motif classes have been added and five existing classes have undergone major revisions. The update includes 411 new motif instances mostly focused on cell-cycle regulation, control of the actin cytoskeleton, membrane remodelling and vesicle trafficking pathways, liquid-liquid phase separation and integrin signalling. Many of the newly annotated motif-mediated interactions are targets of pathogenic motif mimicry by viral, bacterial or eukaryotic pathogens, providing invaluable insights into the molecular mechanisms underlying infectious diseases. The current ELM release includes 317 motif classes incorporating 3934 individual motif instances manually curated from 3867 scientific publications. ELM is available at: http://elm.eu.org.


Subject(s)
Communicable Diseases/genetics , Databases, Protein , Host-Pathogen Interactions/genetics , Protein Interaction Domains and Motifs , Software , Actin Cytoskeleton/chemistry , Actin Cytoskeleton/metabolism , Animals , Binding Sites , Cell Cycle/genetics , Cell Membrane/chemistry , Cell Membrane/metabolism , Communicable Diseases/metabolism , Communicable Diseases/virology , Cyclins/chemistry , Cyclins/genetics , Cyclins/metabolism , Eukaryotic Cells/cytology , Eukaryotic Cells/metabolism , Eukaryotic Cells/virology , Gene Expression Regulation , Humans , Integrins/chemistry , Integrins/genetics , Integrins/metabolism , Mice , Molecular Sequence Annotation , Protein Binding , Rats , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Signal Transduction , Transport Vesicles/chemistry , Transport Vesicles/metabolism , Viruses/genetics , Viruses/metabolism
4.
J Clin Invest ; 131(9)2021 05 03.
Article in English | MEDLINE | ID: covidwho-1223642

ABSTRACT

Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvß6 (ITGß6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGß6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGß6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGß6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.


Subject(s)
Antigens, Neoplasm/biosynthesis , Bile Acids and Salts/metabolism , Biliary Tract/metabolism , Cell Proliferation , Epithelial Cells/metabolism , Integrins/biosynthesis , Macrophage Activation , Macrophages/metabolism , Up-Regulation , Animals , Antigens, Neoplasm/genetics , Bile Acids and Salts/genetics , Female , Humans , Integrins/genetics , Male , Mice , Mice, Transgenic , RNA-Seq
5.
Front Immunol ; 12: 626308, 2021.
Article in English | MEDLINE | ID: covidwho-1190310

ABSTRACT

We have previously shown that conformational change in the ß2-integrin is a very early activation marker that can be detected with fluorescent multimers of its ligand intercellular adhesion molecule (ICAM)-1 for rapid assessment of antigen-specific CD8+ T cells. In this study, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4+ T cells using a monoclonal antibody (clone m24 Ab) specific for the open, high-affinity conformation of the ß2-integrin. The kinetics of ß2-integrin activation was different on CD4+ and CD8+ T cells (several hours vs. few minutes, respectively); however, m24 Ab readily stained both cell types 4-6 h after antigen stimulation. With this protocol, we were able to monitor ex vivo effector and memory CD4+ and CD8+ T cells specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV) in whole blood or cryopreserved peripheral blood mononuclear cells (PBMCs) of infected or vaccinated individuals. By costaining ß2-integrin with m24 and CD154 Abs, we assessed extremely low frequencies of polyfunctional CD4+ T cell responses. The novel assay used in this study allows very sensitive and simultaneous screening of both CD4+ and CD8+ T cell reactivities, with versatile applicability in clinical and vaccination studies.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Host-Pathogen Interactions/immunology , Integrins/metabolism , Adult , Aged , Amino Acid Sequence , Binding Sites , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Carrier Proteins/chemistry , Cytokines/metabolism , Cytomegalovirus/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Female , HLA Antigens/chemistry , HLA Antigens/immunology , Host-Pathogen Interactions/genetics , Humans , Immunohistochemistry , Immunophenotyping , Integrins/genetics , Intercellular Adhesion Molecule-1/chemistry , Intercellular Adhesion Molecule-1/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Protein Binding , Protein Multimerization , SARS-CoV-2/immunology , T-Cell Antigen Receptor Specificity , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
6.
Sci Signal ; 14(665)2021 01 12.
Article in English | MEDLINE | ID: covidwho-1029425

ABSTRACT

The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the µ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin ß3 and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.


Subject(s)
COVID-19/virology , Host Microbial Interactions/physiology , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Virus Internalization , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , Animals , COVID-19/therapy , Conserved Sequence , Host Microbial Interactions/genetics , Humans , Integrins/chemistry , Integrins/genetics , Integrins/physiology , Intrinsically Disordered Proteins/chemistry , Intrinsically Disordered Proteins/genetics , Intrinsically Disordered Proteins/physiology , Models, Biological , Models, Molecular , Oligopeptides/chemistry , Oligopeptides/genetics , Oligopeptides/physiology , Protein Interaction Domains and Motifs/genetics , Protein Interaction Domains and Motifs/physiology , Protein Sorting Signals/genetics , Protein Sorting Signals/physiology , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/physiology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/physiology
7.
J Transl Med ; 19(1): 32, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1015879

ABSTRACT

BACKGROUND: Although it is becoming evident that individual's immune system has a decisive influence on SARS-CoV-2 disease progression, pathogenesis is largely unknown. In this study, we aimed to profile the host transcriptome of COVID-19 patients from nasopharyngeal samples along with virus genomic features isolated from respective host, and a comparative analyses of differential host responses in various SARS-CoV-2 infection systems. RESULTS: Unique and rare missense mutations in 3C-like protease observed in all of our reported isolates. Functional enrichment analyses exhibited that the host induced responses are mediated by innate immunity, interferon, and cytokine stimulation. Surprisingly, induction of apoptosis, phagosome, antigen presentation, hypoxia response was lacking within these patients. Upregulation of immune and cytokine signaling genes such as CCL4, TNFA, IL6, IL1A, CCL2, CXCL2, IFN, and CCR1 were observed in lungs. Lungs lacked the overexpression of ACE2 as suspected, however, high ACE2 but low DPP4 expression was observed in nasopharyngeal cells. Interestingly, directly or indirectly, viral proteins specially non-structural protein mediated overexpression of integrins such as ITGAV, ITGA6, ITGB7, ITGB3, ITGA2B, ITGA5, ITGA6, ITGA9, ITGA4, ITGAE, and ITGA8 in lungs compared to nasopharyngeal samples suggesting the possible way of enhanced invasion. Furthermore, we found comparatively highly expressed transcription factors such as CBP, CEBP, NFAT, ATF3, GATA6, HDAC2, TCF12 which have pivotal roles in lung injury. CONCLUSIONS: Even though this study incorporates a limited number of cases, our data will provide valuable insights in developing potential studies to elucidate the differential host responses on the viral pathogenesis in COVID-19, and incorporation of further data will enrich the search of an effective therapeutics.


Subject(s)
COVID-19/genetics , COVID-19/immunology , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Adult , Aged, 80 and over , COVID-19/virology , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/immunology , Cytokines/genetics , Female , Genetic Variation , Humans , Immunity, Innate/genetics , Integrins/genetics , Lung/immunology , Male , Middle Aged , Models, Immunological , Mutation, Missense , Nasopharynx/immunology , Nasopharynx/virology , Pandemics , RNA-Seq , SARS-CoV-2/isolation & purification , Signal Transduction/genetics , Signal Transduction/immunology , Transcriptome , Translational Research, Biomedical
SELECTION OF CITATIONS
SEARCH DETAIL