Page 20 - MI-1-1

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

protein translation. This temporal regulation of protein 6. Ezrin and cell membrane protein
translation in the endoplasmic reticulum seems to be complex CFTR+EBP50+PKC
controlled by multi-protein complexes at the cell membrane.
It is this delay in the production of RFALT-1/KLF13 protein 6.1. Ezrin peptide RepG3 activates RANTES/CCL5
that causes the 3-day delay in RANTES/CCL5 mRNA expression and secretion
transcription and protein translation. Ezrin protein has a number of functional conformations:
Three days after T-cell activation, two signaling pathways it transforms from an inactive globular form in the
coordinate to trigger the translation of RFLAT-1/KLF13 cytoplasm, to a partially-active transmembrane “receptor”
mRNA into protein. Triggered by cytokines and mitogens, form and on to a fully active elongated submembrane
80
the first kinase cascade commences at phosphoinositide form (Figure 6).
3-kinase (PI3K), which is bound to the alpha domain of Submembrane-active ezrin carries specific attachment
membrane-associated human ezrin protein. Allosteric sites for cell adhesion molecules such as ICAM-1, ICAM-
activation causes PI3K to convert PIP2 into PIP3, which, 3, CD43, and CD44; specific binding sites for kinases
then, phosphorylates PDK1, which, then, phosphorylates such as Ras, RhoA, PKC, PI3K, and PKA; cytoskeleton
and activates AKT/PKB. In the endoplasmic reticulum, components such as actin; and adaptor proteins such as
active AKT/PKB phosphorylates and activates the TSC EBP50, which bind to ion channel proteins such as CFTR.
protein complex. TSC1 phosphorylates and activates the Ezrin peptide RepG3 can bind to an anti-parallel
mTORC1 multiprotein complex containing mTOR. Active alpha-helical Hep-receptor site in the alpha domain of
mTOR then phosphorylates and deactivates a 20-amino human ezrin to induce conformational switching of the
acid protein translation repressor polypeptide called 4E-BP. human ezrin protein, leading to its transformation from
Phosphorylated 4E-BP is forced to detach from eukaryotic the transmembrane receptor conformation of ezrin into
protein translation initiation factor 4E (eIF4E), resulting in the submembrane extended conformation of ezrin, which
a semi-active protein translation initiation factor.
induces multi-protein complexes. The ezrin-assembled
The second kinase cascade is also initiated by allosteric membrane-associated multi-protein-complex appears to
changes in the membrane-associated multi-protein be a biological information processing system that can
complex. Ras kinase, a low-molecular-weight GTP-binding modulate cellular responses to extracellular stimuli. Ezrin-
protein (G protein) bound to the FERM domain of ezrin, based multi-protein-complexes can trigger downstream
activates the ezrin+Ras > Raf > MEK > ERK-1/2 > MNK1 protein-tyrosine-kinase cascades such as Ras > Raf > MEK
signaling cascade. Activated ERK phosphorylates and > ERK1/2 > RSK, as well as PI3K > PDK1 > AKT/PKB >
activates MNK1 in the cytoplasm, which migrates to the mTOR.
endoplasmic reticulum and then rapidly phosphorylates
and fully activates free eIF4E. Active eIF-4E, then, 6.2. CFTR+EBP50+PKC+ezrin regulation of RANTES/
mediates the assembly of ribosomal components at the CCL5 gene expression
five-prime end of the mRNA into functional ribosomes. The cystic fibrosis transmembrane regulator (CFTR)
Activated eIF4E interacts directly with the five-prime- plays an important role in the regulation of mucosal
end cap-structure of RFLAT-1/KLF13 mRNA to form immunity to infection in airway epithelia. CFTR and
a ribosomal translation initiation complex with eIF4A, EPB50, also known as Na /H -exchanger regulatory
+
+
eIF3, eIF4G, PABP, and MNK1. The new ribosome, then, factor 1 (NHERF1), form a signaling complex with the
initiates translation of mRNA into the transcription factor FERM domain of ezrin, which is directly connected to the
RFLAT-1/KLF13 protein. ezrin alpha domain, containing specific binding sites for
The new transcription factor RFLAT-1/KLF13 migrates signaling initiators PKC, PI3K, and PKA. Activated ezrin
to the nucleus and binds to the –71bp to –53bp “A” site assembles CFTR+EBP50+ICAM+Ezrin+PKC+PI3K into
gene promoter of the RANTES/CCL5 gene, where it a multiprotein complex at the membrane, which initiates a
assembles a transcription complex. The RANTES/CCL5 range of signals in the cell interior.
gene transcription into mRNA increases more than ten- It is well known that CFTR functions as a cyclic AMP-
fold, and the new RANTES/CCL5 mRNA migrates back regulated chloride-ion Cl- channel. As part of a multi-
to the endoplasmic reticulum. RANTES/CCL5 mRNA is protein complex with ezrin, CFTR also regulates the
then translated into a 91-amino acid pre-cursor protein adjacent epithelial sodium ion channel Na /H exchanger
+
+
that is cleaved to form a 68-amino acid RANTES/CCL5 (NHE), which removes intracellular protons in exchange
polypeptide, which is excreted from the cell through the for extracellular sodium. However, CFTR triggers
Golgi apparatus. 79 RANTES/CCL5 mRNA expression through a mechanism

Volume 1 Issue 1 (2024) 14 doi: 10.36922/mi.2474