PMID- 27998979
OWN - NLM
STAT- MEDLINE
DCOM- 20170601
LR  - 20210314
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 292
IP  - 5
DP  - 2017 Feb 3
TI  - alpha Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-mediated Transactivation 
      and Transrepression in Podocytes.
PG  - 1637-1647
LID - S0021-9258(20)36696-5 [pii]
LID - 10.1074/jbc.M116.755546 [doi]
AB  - Glucocorticoids are a general class of steroids that possess renoprotective 
      activity in glomeruli through their interaction with the glucocorticoid receptor. 
      However, the mechanisms by which glucocorticoids ameliorate proteinuria and 
      glomerular disease are not well understood. In this study, we demonstrated that alpha 
      actinin 4 (ACTN4), an actin-cross-linking protein known to coordinate 
      cytoskeletal organization, interacts with the glucocorticoid receptor (GR) in the 
      nucleus of human podocytes (HPCs), a key cell type in the glomerulus critical for 
      kidney filtration function. The GR-ACTN4 complex enhances glucocorticoid response 
      element (GRE)-driven reporter activity. Stable knockdown of ACTN4 by shRNA in 
      HPCs significantly reduces dexamethasone-mediated induction of GR target genes 
      and GRE-driven reporter activity without disrupting dexamethasone-induced nuclear 
      translocation of GR. Synonymous mutations or protein expression losses in ACTN4 
      are associated with kidney diseases, including focal segmental 
      glomerulosclerosis, characterized by proteinuria and podocyte injury. We found 
      that focal segmental glomerulosclerosis-linked ACTN4 mutants lose their ability 
      to bind liganded GR and support GRE-mediated transcriptional activity. 
      Mechanistically, GR and ACTN4 interact in the nucleus of HPCs. Furthermore, 
      disruption of the LXXLL nuclear receptor-interacting motif present in ACTN4 
      results in reduced GR interaction and dexamethasone-mediated transactivation of a 
      GRE reporter while still maintaining its actin-binding activity. In contrast, an 
      ACTN4 isoform, ACTN4 (Iso), that loses its actin-binding domain is still capable 
      of potentiating a GRE reporter. Dexamethasone induces the recruitment of ACTN4 
      and GR to putative GREs in dexamethasone-transactivated promoters, SERPINE1, 
      ANGPLT4, CCL20, and SAA1 as well as the NF-kappaB (p65) binding sites on 
      GR-transrepressed promoters such as IL-1beta, IL-6, and IL-8 Taken together, our 
      data establish ACTN4 as a transcriptional co-regulator that modulates both 
      dexamethasone-transactivated and -transrepressed genes in podocytes.
CI  - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Zhao, Xuan
AU  - Zhao X
AD  - From the Department of Biochemistry, Case Western Reserve University School of 
      Medicine, Cleveland, Ohio 44106.
FAU - Khurana, Simran
AU  - Khurana S
AD  - From the Department of Biochemistry, Case Western Reserve University School of 
      Medicine, Cleveland, Ohio 44106.
FAU - Charkraborty, Sharmistha
AU  - Charkraborty S
AD  - From the Department of Biochemistry, Case Western Reserve University School of 
      Medicine, Cleveland, Ohio 44106.
FAU - Tian, Yuqian
AU  - Tian Y
AD  - From the Department of Biochemistry, Case Western Reserve University School of 
      Medicine, Cleveland, Ohio 44106.
FAU - Sedor, John R
AU  - Sedor JR
AD  - Rammelkamp Center for Education and Research and Department of Medicine, 
      MetroHealth Medical Center, Case Western Reserve University School of Medicine, 
      Cleveland, Ohio 44106.
FAU - Bruggman, Leslie A
AU  - Bruggman LA
AD  - Rammelkamp Center for Education and Research and Department of Medicine, 
      MetroHealth Medical Center, Case Western Reserve University School of Medicine, 
      Cleveland, Ohio 44106.
FAU - Kao, Hung-Ying
AU  - Kao HY
AD  - From the Department of Biochemistry, Case Western Reserve University School of 
      Medicine, Cleveland, Ohio 44106; Case Comprehensive Cancer Center, Case Western 
      Reserve University School of Medicine, Cleveland, Ohio 44106. Electronic address: 
      hxk43@cwru.edu.
LA  - eng
GR  - R01 DK078965/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20161220
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ACTN4 protein, human)
RN  - 0 (Cytokines)
RN  - 0 (Protein Isoforms)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 11003-00-2 (Actinin)
RN  - 7S5I7G3JQL (Dexamethasone)
SB  - IM
MH  - Actinin/*biosynthesis/genetics
MH  - Cytokines/biosynthesis/genetics
MH  - Dexamethasone/*pharmacology
MH  - HEK293 Cells
MH  - HeLa Cells
MH  - Humans
MH  - Podocytes/cytology/*metabolism
MH  - Protein Isoforms/biosynthesis/genetics
MH  - Receptors, Glucocorticoid/agonists/genetics/*metabolism
MH  - Response Elements/*physiology
MH  - Transcriptional Activation/*drug effects
PMC - PMC5290941
OTO - NOTNLM
OT  - Glucocorticoid receptor
OT  - podocyte
OT  - transactivation
OT  - transcription coactivator
OT  - transcription corepressor
OT  - translation control
OT  - transrepression
OT  - alpha actinin 4
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2016/12/22 06:00
MHDA- 2017/06/02 06:00
PMCR- 2018/02/03
CRDT- 2016/12/22 06:00
PHST- 2016/08/25 00:00 [received]
PHST- 2016/12/19 00:00 [revised]
PHST- 2016/12/22 06:00 [pubmed]
PHST- 2017/06/02 06:00 [medline]
PHST- 2016/12/22 06:00 [entrez]
PHST- 2018/02/03 00:00 [pmc-release]
AID - S0021-9258(20)36696-5 [pii]
AID - M116.755546 [pii]
AID - 10.1074/jbc.M116.755546 [doi]
PST - ppublish
SO  - J Biol Chem. 2017 Feb 3;292(5):1637-1647. doi: 10.1074/jbc.M116.755546. Epub 2016 
      Dec 20.