title: Familial focal segmental glomerulosclerosis (FSGS)-linked α-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors.
abstract: 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.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University and Research Institute of University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
authors.forename: Simran
authors.initials: S
authors.lastname: Khurana
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Chakraborty
authors.forename: Minh
authors.initials: M
authors.lastname: Lam
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Su
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Bruggeman
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Kao
mesh_terms: D000185:Actinin / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics*; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense; D047495:PPAR gamma / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014212:Tretinoin / Q000502:physiology
chemical_list: C111453:ACTN4 protein, human; D050505:Mutant Proteins; D047495:PPAR gamma; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D000072482:Retinoic Acid Receptor alpha; D000185:Actinin; D014212:Tretinoin