Alpha actinin 4 potentiates nuclear NF-{kappa}B activity in podocytes independent of its cytoplasmic actin binding function [Molecular Bases of Disease]

November 19th, 2014 by Zhao, X., Hsu, K.-S., Lim, J. H., Bruggeman, L. A., Kao, H.-Y.

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-κB pathway in podocytes is implicated in glomerular diseases including proteinuria. We demonstrate here that stable knockdown of ACTN4 in podocytes significantly reduces TNFα-mediated induction of NF-κB target genes,including IL-1[beta] and NPHS1, and activation of a NF-κB-driven reporter without interfering with p65 nuclear translocation. Overexpression of ACTN4 and an actin binding-defective variant increase 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-κB activity. Mechanistically, I[kappa]B[alpha] blocks the association of ACTN4 and p65 in the cytosol. In response to TNF[alpha], both NF-[kappa]B subunits p65 and p50 translocate to the nucleus, where they bind and recruit ACTN4 to their targeted promoters, IL-1[beta] and IL-8. Taken together, our data identify ACTN4 as a novel coactivator for NF-κB transcription factors in podocytes. Importantly, this nuclear function of ACTN4 is independent of its actin-binding activity in the cytoplasm.
  • Posted in Journal of Biological Chemistry, Publications
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