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Microbes & Immunity RANTES/CCL5 and ezrin peptide RepG3 for long COVID

Figure 6. Ezrin peptide RepG3 induces ezrin active form. Soluble globular ezrin is an inactive form of ezrin present in the cytoplasm. Increasing PIP2
concentrations at the inner surface of the cell membrane cause ezrin to bind and partly unfold into a transmembrane “receptor” conformation. Further
increases in PIP2 concentrations in the membrane (not shown for clarity) induced an elongated ezrin active form, which is wholly attached to the sub-
membrane surface. RepG3, a synthetic fragment of the ezrin alpha domain, induces the ezrin active form (the position numbers from the primary protein
sequence of ezrin, locate certain amino acids in the various tertiary protein structures). RepG3 peptide and its homologous sequence in the ezrin protein
chain are marked in blue, while the regions containing a high frequency of hydrophobic amino acids are marked in orange.

that is separate from CFTR’s chloride-ion channel activity: Experiments with mutants of CFTR show that
neither pharmacological inhibition of CFTR chloride transcription factor activation and RANTES/CCL5
channels nor activation of alternative chloride channels expression require functional CTFR inserted in a cell-
are involved in the modulation of RANTES/CCL5 mRNA membrane multi-protein-complex with ezrin, in which
expression. Accumulating evidence suggests that the the CFTR C-terminal PDZ-interacting domain is engaged
allosteric effects of ezrin-based multiprotein complexes with other proteins of the complex. In airway epithelial
control the expression of RANTES/CCL5 in airway cell cultures of CF cells from cystic fibrosis patients, the
epithelial cells and other cell types, as shown in the diagram mutation of CTFR prevents RANTES/CCL5 mRNA
below. expression, and neither TNF-α nor INF-γ stimulation can
In normal CFTR-expressing cells, CFTR-mediated restore it. In contrast, the insertion of wild-type CFTR into
signaling activates the transcription factor CREB to bind CF airway epithelial cells corrects the defect and results in
to the cAMP-responsive element (CRE) of the RANTES/ the restoration of RANTES/CCL5 mRNA expression.
CCL5 gene (upstream of the NF-κB promoter site), which Ezrin-binding phosphoprotein 50 is also involved
maintains constitutive expression of RANTES/CCL5 in modulating the CFTR control of NF-κB activation
mRNA in resting cells. This CREB-mediated mRNA and NF-κB-mediated expression of RANTES/CCL5.
expression of the RANTES/CCL5 gene cannot be further Ezrin-binding phosphoprotein 50 also modulates the
enhanced by either TNF-α cytokine stimulation or NF-κB activity of the transcription factors NFAT and NF-IL-6,
activation. which regulate RANTES/CCL5 gene transcription in the

Volume 1 Issue 1 (2024) 15 doi: 10.36922/mi.2474