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ABCE1 is the only member of the E subfamily of the ABC superfamily. ABCE1 is mainly found in cytoplasm and mitochondria and is widely distributed in archaea and eukaryotes, originally found in mammals. In the human body, its genes are widely expressed in various organs: high expression in brain, kidney and prostate, low expression in liver, spleen, colon, heart muscle and skeletal muscle tissue, but not in spinal cord and bone.
ABCE1 has two isoforms. It consists of two ATP-binding regions at the C-terminus and an N-terminal Fe-S cluster. The former is a protein folding region (NBDs) capable of binding nucleotides. Both NBDs have a typical bilobular ABC-type ATPase region and an ATP-binding region ABCE1. The ATP-binding region contains WalkerA, WalkerB, aromatic amino acid ring (Tyr-loop), glutamate ring (Gln-loop), histamine, His-loop, the transporter signal motif (signature C), and the last four motifs are hallmarks of the ABC superfamily.
The highly conserved N-terminal region rich in cysteine is the structure of ABCE1 unique to the ABC superfamily. Both Fe-S clusters are coordinated with four cysteines, respectively. The cysteine residue acts by forming two diamagnetic Fe - S clusters with Fe ions. Seven of the eight cysteine residues are indispensable for Fe-S cluster function, and their variation will result in cell death.
Figure 1. Rli1/ABCE1 recycles terminating ribosomes and controls translation reinitiation in 30 UTRs in vivo. (Young, D. J., et al. 2015)
Protein Synthesis of ABCE1
ABCE1 is primarily involved in the initiation, termination, and ribosome circulation of translation. Protein translation begins with the 60S ribosomal subunit and the 40S ribosomal sub-based on the initiation factor to form a biologically active 80S ribosome. The initiation factor eIF plays an important role in the initiation. The study found that ABCE1 promotes the function of eIF3 by an unknown mechanism, and found that ABCE1 binds to the initiation factors eIF2 and eIF5 to form part of PIC, which is required for yeast mRNA translation.
Another study by Beznosková et al. shows that ABCE1 can promote the termination of the translation process without relying on ATP, but the specific mechanism remains unclear. However, lowering the ABCE1 level and increasing the yeast termination password read-through phenomenon is consistent with the proposal that ABCE1 has a termination password recognition function. Studies have shown that ABCE1 interacts with eRF1 to affect eRF1 termination codon recognition and peptidyl tRNA hydrolysis. Preis et al. found that ABCE1 binds to eRF1-loaded ribosomes to promote peptide release and dissociation of ribosomal subunits.
ABCE1 has also been shown to promote ribosomal circulation in higher eukaryotes. When translation is terminated, pre-TC consisting of eukaryotic 80S ribosomes, P-position acyl tRNA, and eRF1 can be dissociated in a non-energy-dependent manner by binding to eIF3, eIF1, eIF1A, but requires a very narrow range of magnesium ion concentrations. However, ABCE1 promotes the dissociation of the complex into the 60S ribosomal subunit and the 40S subunit under a wide range of magnesium ion concentrations, thereby promoting ribosome circulation. However, ABCE1 can only be combined with pre-TC that has been bound by eRF1 /eRF3 or eRF1, since eIF3, eIF1, and eIF1A are required to dissociate mRNA and tRNA from the 40S subunit. Kashima et al. found in the genus Drosophila, when ribosomes encounter mRNAs lacking a stop codon, ABCE1 plays an important role in the mechanism of non-terminating mRNA decline.
ABCE1 and Disease
Studies in colon cancer have found that the ABCE1 gene-encoded polypeptide induces HLA-A2-restricted and tumor-reactive cytotoxic T lymphocyte production. This suggests that ABCE1 protein can be a specific immunotherapeutic target for HLA-A2-positive colon cancer patients. In the study of malignant melanoma, the expression of ABCE1 gene in malignant melanoma cells was significantly increased compared with melanocytes. In human hepatoma cells, studies have also shown that ABCE1 is significantly increased, and its gene level is regulated by microRNA (miRNA), namely miR-203. Therefore, the application of miRNA therapy can play an anti-tumor effect.
Huang et al. detected the expression of ABCE1 in esophageal cancer tissues by contrast and introduced the siRNA green fluorescent protein expression vector carrying ABCE1 into esophageal cancer Eca109 cells. The study found that the expression of ABCE1 in esophageal cancer tissues was significantly higher than that in adjacent tissues. And the lower the differentiation level, the negative expression of ABCE1 expression level and tissue differentiation. ABCE1 may affect the development of esophageal cancer through regulation of the 2-5A/RNase L pathway.
In the study, ABCE1-siRNA was constructed and transfected into 95-D/NCL-H446 cells. It was found that the transfected tumor cells had decreased proliferation and apoptotic rate, and the expression of E-cadherin increased and the infiltration decreased. Huang et al. transferred ABCE1-siRNA into the small cell lung cancer line NCL-H446, which decreased proliferation, invasion, and migration. Gong research found that after inhibiting the expression of ABCE1 in large cell lung cancer H460 cells, the cell proliferation was significantly decreased, the apoptotic rate was increased, and the RNase L protein was significantly increased. Kara et al. confirmed that down-regulation of ABCE1 increased the sensitivity of A549 lung cancer cells to chemotherapy drugs.