Document text
Principal Investigator: Jieqing Zhu
Organization: VERSITI BLOOD HEALTH, INC.
Fiscal Year: 2024
Award: $718,854
Funding agency: National Heart Lung and Blood Institute
SUMMARY – Integrins interact with their ligands to induce intracellular signals that mediate cellular activities
such as cell adhesion, spreading, and migration, which are the essential cellular activities for the function of
blood and endothelial cells. These signaling events are typically mediated by the cytoplasmic tail of integrin β
subunit, while the role of α integrin cytoplasmic tail in integrin function remains relatively underexplored. Our
research found that the fibronectin receptor integrin α5β1, via its α cytoplasmic tail, is involved in the formation of
tunneling nanotubes (TNTs), a novel type of cellular structure for cell-to-cell communication. Remarkably, our
research found that the α5β1-mediated TNT formation can be induced by the spike protein of coronavirus SARS-
CoV-2. We observed the spike-induced and α5-dependent TNT formation in model cell lines and primary human
blood and endothelial cells. Furthermore, we found that α5β1 integrin can mediate the spike-induced
proinflammatory response in human blood and endothelial cells, which may contribute to the thrombotic events
in COVID-19. TNTs are long actin-rich cell membrane protrusions that have been increasingly recognized as
functional subcellular structures for long-distance dynamic intercellular connection. Functioning as conduits
between connected cells, TNTs can transport cytoplasmic components like small molecules, proteins, vesicles,
and mitochondria intercellularly. Accumulating evidence suggests that TNTs are involved in the progress of many
pathological conditions such as cancer, inflammation, and neurodegenerative diseases. Bacteria and virus
pathogens also exploit TNTs for cell-to-cell transmission. TNTs can form under cell stress conditions such as
inflammation and virus infection. However, the cellular mechanisms regulating TNT formation remain largely
unknown. This is mainly because little to nothing is known about the cell surface receptors directly responsible
for TNT biogenesis. Our discovery of α5β1 integrin as a functional signaling receptor for TNT formation provides
a powerful platform for investigating TNT biology. Mechanistically, we found that both α5β1-mediated TNT
formation and proinflammatory response require the participation of α5 cytoplasmic tail, suggesting that these
two processes are interconnected events. Moreover, our protein interaction data suggest a direct binding
between α5β1 and the spike protein, which is independent of the classical integrin recognition Arg-Gly-Asp (RGD)
motif. Based on these promising data, this application aims to elucidate the cellular mechanisms governing the
non-conventional signaling function of α5β1 integrin in TNT formation and inflammation in blood and endothelial
cells. Multifaced biochemical, biophysical, structural and cell biology approaches will be used to identify
intracellular molecules and signaling pathways involved in the α5β1-mediated TNT formation (Aim 1) and
inflammation (Aim 2) and to characterize the non-RGD dependent α5β1 and ligand interaction (Aim 3). The
outcome of this study will advance both integrin and TNT biology and uncover potential therapeutic targets for
modulating TNTs and inflammation in various diseases.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Actins><Address><Adhesion Molecule><Antibodies><Arg-Gly-Asp><Arginine-Glycine-Aspartic Acid Cell Adhesion Domain><Assay><Attenuated><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Binding><Binding Proteins><Binding Sites><Bioassay><Biochemical><Biogenesis><Biological Assay><Biology><Biophysics><Blood Cells><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><CD49e Antigens><COVID-19><COVID-19 S protein><COVID-19 pathogenesis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 pathogenesis><COVID19 virus><CV-19><Cancers><Cell Adhesion><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Components><Cell Function><Cell Growth in Number><Cell Interaction><Cell Line><Cell Membrane Extensions><Cell Membrane Projections><Cell Membrane Protrusions><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cell Structure><Cell Surface Extensions><Cell Surface Projections><Cell Surface Protrusions><Cell Surface Receptors><Cell Survival><Cell Viability><Cell membrane><Cell model><Cell surface><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cell-Extracellular Matrix><Cell-to-Cell Interaction><CellLine><Cells><Cellular Adhesion><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular Stress><Cellular Stress Response><Cellular Structures><Cellular biology><Cellular model><Chemicals><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Combining Site><Comparative Study><Coronavirus Infectious Disease 2019><Coronavirus glycoprotein S><Coronavirus spike protein><Cytoplasm><Cytoplasmic Domain><Cytoplasmic Membrane><Cytoplasmic Tail><Data><Degenerative Neurologic Disorders><Development><Disease><Disorder><ECM><Electron Microscopy><Endothelial Cells><Event><Extracellular Matrix><FNRA><Family><Fibronectin Receptor><Fibronectin Receptor Alpha Subunit><Fibronectin Receptors><Genetics-Mutagenesis><HPGF><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><ITGA5><ITGA5 gene><Immune response><Immunological response><Infection><Inflammation><Inflammatory><Inflammatory Response><Integrin Alpha 5><Integrin Binding><Integrin alpha Chains><Integrin alpha Subunits><Integrin alpha-5 beta-1><Integrin alpha5><Integrin alpha5beta1><Integrin alphaF><Integrin beta Chains><Integrin beta Subunits><Integrin α Subunits><Integrin α5><Integrin α5β1><Integrin β Chains><Integrin β Subunits><Integrins><Integrins Extracellular Matrix><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Intracellular Communication and Signaling><Intracellular Structure><Knock-out><Knockout><Label><Lead><Ligand Binding><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Lung><Lung Respiratory System><MGI-2><Macrophage><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Membrane><Mitochondria><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Sieve Chromatography><Molecular Stereochemistry><Mutagenesis><Mutagenesis Molecular Biology><Myeloid Differentiation-Inducing Protein><Mφ><Nanotubes><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Origin of Life><Outcome Study><Pathologic><Pathway interactions><Pb element><Peripheral Blood Cell><Phase><Physiologic><Physiological><Plasma Membrane><Plasmacytoma Growth Factor><Platelet Glycoprotein Ic><Platelet Glycoprotein Ic/IIa><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preinterleukin 1 Beta><Process><Protein Binding><Proteins><RGD (sequence)><RGD Cell Adhesion Domain><RGD Domain><RGD Motif><RGD Tripeptide Sequence><RGD peptide><RGD tripeptide><Reactive Site><Receptor Signaling><Regulation><Research><Research Resources><Resources><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Size Exclusion Chromatography><Solid><Strains Cell Lines><Subcellular Process><Subcellular structure><Thrombosis><Transmission><Umbilical vein><VLA-5><VLA-5 Receptors><VLA-5 alpha Chain><VLA5A><Vascular Endothelial Cell><Vesicle><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><alpha Integrins><alpha(5) Integrin><angiogenesis><arginyl-glycyl-aspartic acid><attenuate><attenuates><bacteria pathogen><bacterial pathogen><beta Integrins><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><bound protein><cell adhesion protein><cell biology><cell stress><cell type><conformation><conformational><conformational state><conformationally><conformations><coronavirus S protein><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 pathogenesis><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus spike glycoprotein><crosslink><cultured cell line><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><design and construct><design and construction><developmental><hCoV19><heavy metal Pb><heavy metal lead><host response><immune system response><immunoresponse><innovate><innovation><innovative><integrin bound><intercellular communication><intercellular connection><interferon beta 2><knockout gene><light scattering><malignancy><member><membrane structure><migration><mitochondrial><nCoV2><nanobodies><nanobody><neoplasm/cancer><neurodegenerative illness><neutrophil><novel><pathogenic bacteria><pathogenic virus><pathway><phosphodiesterase 4D><plasmalemma><progenitor cell differentiation><progenitor differentiation><protein purification><pulmonary><receptor binding><receptor bound><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><sdAb><single domain antibodies><small molecule><social role><spike proteins on SARS-CoV-2><stem and progenitor differentiation><stem cell differentiation><structural biology><therapeutic target><thrombotic><thrombotic disease><thrombotic disorder><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><transmission process><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><α-Integrins><β-Integrins>