| First Author | Zhao X | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 1 | Pages | 338-49 |
| PubMed ID | 25411248 | Mgi Jnum | J:221512 |
| Mgi Id | MGI:5640903 | Doi | 10.1074/jbc.M114.597260 |
| Citation | Zhao X, et al. (2015) alpha-Actinin 4 potentiates nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-kappaB) activity in podocytes independent of its cytoplasmic actin binding function. J Biol Chem 290(1):338-49 |
| abstractText | Glomerular podocytes are highly specialized terminally differentiated cells that act as a filtration barrier in the kidney. Mutations in the actin-binding protein, alpha-actinin 4 (ACTN4), are linked to focal segmental glomerulosclerosis (FSGS), a chronic kidney disease characterized by proteinuria. Aberrant activation of NF-kappaB pathway in podocytes is implicated in glomerular diseases including proteinuria. We demonstrate here that stable knockdown of ACTN4 in podocytes significantly reduces TNFalpha-mediated induction of NF-kappaB target genes, including IL-1beta and NPHS1, and activation of an NF-kappaB-driven reporter without interfering with p65 nuclear translocation. Overexpression of ACTN4 and an actin binding-defective variant increases the reporter activity. In contrast, an FSGS-linked ACTN4 mutant, K255E, which has increased actin binding activity and is predominantly cytoplasmic, fails to potentiate NF-kappaB activity. Mechanistically, IkappaBalpha blocks the association of ACTN4 and p65 in the cytosol. In response to TNFalpha, both NF-kappaB subunits p65 and p50 translocate to the nucleus, where they bind and recruit ACTN4 to their targeted promoters, IL-1beta and IL-8. Taken together, our data identify ACTN4 as a novel coactivator for NF-kappaB transcription factors in podocytes. Importantly, this nuclear function of ACTN4 is independent of its actin binding activity in the cytoplasm. |
