Identification of a Novel LXXLL Motif in α-Actinin 4-spliced Isoform That Is Critical for Its Interaction with Estrogen Receptor α and Co-activators

Abstract

Background: ACTN4 potentiates nuclear receptor (NR)-mediated transcriptional activity. Results: The flanking sequences to the LXXLL motif in ACTN4 are important for both its association with ER␣ and co-activators. Conclusion: The ACTN4 (Iso) acts as a more potent co-activator of NRs than the corresponding ACTN4 (full length) through stronger interactions with known co-activators. Significance: This study describes a novel molecular mechanism by which ACTN4 (Iso) regulates transcription mediated by NRs.

α-Actinin 4 Potentiates Nuclear Factor κ-Light-chain-enhancer of Activated B-cell (NF-κB) Activity in Podocytes Independent of Its Cytoplasmic Actin Binding Function

“…6D). This is consistent with our previous report that Gal-ACTN4 (Iso) has a higher transactivation activity than the wild-type protein, likely due to a better binding activity of ACTN4 (Iso) to p160 coactivators and the histone acetyltransferase activity PCAF than the ACTN4 (FL) (10).…”

“…This finding was recently confirmed by An et al (8). We also established that ACTN4 has a regulatory function on transcription mediated by nuclear hormone receptors such as estrogen receptor, retinoic acid receptor, peroxisome proliferator-activated receptor, and vitamin D receptor via its N-terminal nuclear receptor-interacting motif, LXXLL (9,10). Notably, FSGS-linked ACTN4 mutants, which are predominantly cytoplasmic, lose their ability to potentiate hormone-dependent transcriptional activation (11).…”

“…When tethered to the Gal4 DNA-binding domain (DBD), Gal DBD-ACTN4 potently activates Gal4 reporter activity, likely through its interaction with transcriptional coactivators such as p160 coactivators and the histone acetyltransferase activity p300/ CBP-associated factor (PCAF) (10). Our current study provides strong evidence demonstrating that 1) ACTN4 is essential for NF-B-mediated transcriptional activation, 2) ACTN4 interacts with p65 and p50 in the nucleus and is recruited to the promoters of NF-B target genes, IL-1␤ and IL-8, 3) loss of lanes 1-6).…”

α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation and Transrepression in Podocytes

“…ACTN4 Potentiates and Interacts with GR␣ in a Ligand-dependent Manner-We have previously demonstrated that ACTN4 is a transcriptional coactivator for several transcription factors, including NRs (31). To test whether GR and ACTN4 interact in kidney cells, we carried out immunoprecipitation to examine whether endogenous GR and ACTN4 interact in HEK293T cells.…”

ACTN4 (actinin, alpha 4)

“…ii/ Modulation of gene transcription. It has been shown that α-actinin 4 interacts with nuclear receptors (estrogen receptor α in MCF-7 cells, vitamin D receptor in CV-1 cells, retinoic acid receptor and peroxisome proliferator-activated receptor γ in podocytes) and transcriptional co-activators (PCAF, SRC-1) through its LXXLL motif (Khurana et al, 2012a;Khurana et al, 2012b). Binding affinity to the nuclear factors was stronger in the alternatively spliced (short) isoform identified in a human cDNA library during earlier study (Chakraborty et al, 2006).…”