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α- Actinin 4(ACTN4) form antiparallel aligned head to a tail homodimer of two identical coupled to the peptide chain. ACTN4 consists of three domains: (1) the N-terminal actin-binding domain (ABD), which contains 250 amino acid residues. This region is highly stable in evolution and is involved in the binding of actin. (2) The central rod-like domain, which consists of four spectroscopy alpha-helix repeats, each containing 122 amino acid residues. (3) Two "EF-hand" Ca 2 + domains at the C-terminus, which contain 150 amino acid residues. Therefore, there is an ABD at both ends of the ACTN4 molecule to cross actin.
Figure 1. Cellular distribution of protein complexes that include actinin-4. (Honda, et al. 2015)
ACTN4 and Ovarian Cancer
It has been reported that ACTN4 is closely related to the occurrence, development, and prognosis of malignant tumors such as lung cancer, breast cancer, and pancreatic cancer. Studies have shown that 265 cases of different types of primary ovarian cancer using immunohistochemical techniques found that ACTN4 is highly expressed in 57% of cases, and the expression level is highly correlated with serous histological subtype (P = 0.0075). Among them, ACTN4 was highly expressed in patients with higher histological stage, deeper disease progression, and larger in situ tumors. ACTN4 high expression was associated with elevated levels of E-cadherin and β-catenin levels. The 5-year survival rate (52.4%) was significantly lower in patients with high ACTN4 expression than in the low-expression group (71.9%). ACTN4 protein localization is only 7.5% of nuclear pathology, and these patients have a lower histological stage. Studies have shown that 138 cases of ovarian cancer by fluorescence in situ hybridization (FISH) found that ACTN4 expression ≥ 4 copies in 21% of cases. These high expression groups also showed strong ACTN4 immunoreactivity, high tumor histopathological stage, strong primary chemotherapy resistance, large primary tumor lesions, and poor prognosis. The main histological type is clear cell carcinoma. Studies have shown that the amplification of ACTN4 gene is more predictive of prognostic risk than the immunohistochemical analysis of ACTN4 (related risk 2.48:1.55).
ACTN4 and Focal Segmental Glomurular Sclerosis
Focal segmental glomurular sclerosis (FSGS) is a chronic nephrotic syndrome caused by renal podocyte dysfunction. Bartram et al. performed a second generation ACTN4 sequencing of a child with FSGS to detect a novel p.g195d disease-causing mutation. At the same time, the expression level of ACTN 4 in urothelial cells was lower than that in healthy children. Studies have shown that 10 patients with renal involvement in a familial FSGS family were subjected to PCR for ACTN4 gene knock-on analysis, and found that ACTN4 in this family had 184T > A (S62T) mutations. This suggests that mutations in ACTN4 may be one of the genes involved in familial FSGS. Read et al. have found that ubiquitin C terminal hydrolase L1 deletion maintains the integrity of the podocyte cytoskeleton and protects the glomerular filtration barrier, thereby improving glomerular damage in ACTN4-related FSGS mice.
ACTN4 and Minimal Change Nephrosis (MCD)
ACTN4 was detected in the renal tissues of 6 children with MCD. The expression level of ACTN4 mRNA was similar to that of the normal control group. The study found that the expression level of ACTN4 protein in kidney tissue of children with MCD was not different from that of normal children. However, in mice in vitro, it was found that the expression of ACTN4 mRNA in the kidney tissue of MCD mice began to be up-regulated on the 20th day, which was later than that of podocyte protein and phenylephrine mRNA. At the same time, its distribution in mouse glomeruli changed from the original dotted line distribution to a continuous linear distribution. Safaříková et al. screened the ACTN4 gene in 48 unrelated FSGS and MCD patients, and found 2242A > G (p. Asn748Asp) substitution mutation in 1 patient. At the same time, 2351C > T (p. Ala784Val), 2378G > A (p. Cys793Tyr) and 2393G > A (p. Gly798Asp) were found in patients with IgA nephropathy, but these mutations were not found in 200 healthy subjects.
Application of ACTN4 in the Treatment of Kidney Diseases
The study found that hyperglycemia and high glycation end products have an effect on the expression and distribution of ACTN4 in podocytes, while ginseng total saponins can restore the expression of α-actinin 4 in podocytes. Studies have shown that immunosuppressive agents are used to treating patients with proliferative and non-proliferative glomerular diseases. After 6 months, the expression of ACTN4 in glomerular podocytes is reduced. In addition, glucocorticoid receptor interacts with ACTN4 in the nucleus of podocytes, and dexamethasone induces the interaction of ACTN4 with this receptor to form ACTN4 transcriptional co-regulatory factor, thereby protecting glomerular podocytes. The expression and distribution of ACTN4 are closely related to podocyte injury, which may be a nephrotoxic drug and a target protein for the treatment of kidney disease. However, its specific application and mechanism of action in the prevention, diagnosis, and treatment of kidney disease remains to be further studied.