Familial focal segmental glomerulosclerosis (FSGS)-linked α-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors

J Biol Chem. 2012 Apr 6;287(15):12027-35. doi: 10.1074/jbc.M112.345421. Epub 2012 Feb 17.


Mutations in α-actinin 4 (ACTN4) are linked to familial forms of focal segmental glomerulosclerosis (FSGS), a kidney disease characterized by proteinuria due to podocyte injury. The mechanisms underlying ACTN4 mutant-associated FSGS are not completely understood. Although α-actinins are better known to cross-link actin filaments and modulate cytoskeletal organization, we have previously shown that ACTN4 interacts with transcription factors including estrogen receptor and MEF2s and potentiates their transcriptional activity. Nuclear receptors including retinoic acid receptor (RAR) have been proposed to play a protective role in podocytes. We show here that ACTN4 interacts with and enhances transcriptional activation by RARα. In addition, FSGS-linked ACTN4 mutants not only mislocalized to the cytoplasm, but also lost their ability to associate with nuclear receptors. Consequently, FSGS-linked ACTN4 mutants failed to potentiate transcriptional activation by nuclear hormone receptors in podocytes. In addition, overexpression of these mutants suppressed the transcriptional activity mediated by endogenous wild-type ACTN4 possibly by a cytoplasmic sequestration mechanism. Our data provide the first link between FSGS-linked ACTN4 mutants and transcriptional activation by nuclear receptor such as RARα and peroxisome proliferator-activated receptor γ.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actinin / genetics*
  • Actinin / metabolism
  • Cell Line
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Humans
  • Mutant Proteins / metabolism
  • Mutation, Missense*
  • PPAR gamma / metabolism
  • Podocytes / metabolism
  • Protein Binding
  • Protein Transport
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Proteins / metabolism
  • Retinoic Acid Receptor alpha
  • Transcription, Genetic*
  • Transcriptional Activation
  • Tretinoin / physiology


  • ACTN4 protein, human
  • Mutant Proteins
  • PPAR gamma
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Recombinant Proteins
  • Retinoic Acid Receptor alpha
  • Actinin
  • Tretinoin