PMID- 33895141
OWN - NLM
STAT- MEDLINE
DCOM- 20210819
LR  - 20220111
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 296
DP  - 2021 Jan-Jun
TI  - Sp1 is a substrate of Keap1 and regulates the activity of CRL4A(WDR23) ubiquitin 
      ligase toward Nrf2.
PG  - 100704
LID - S0021-9258(21)00493-2 [pii]
LID - 10.1016/j.jbc.2021.100704 [doi]
LID - 100704
AB  - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical transcription 
      factor that orchestrates cellular responses to oxidative stress. Because the 
      dysregulation of Nrf2 has been implicated in many diseases, precise regulation of 
      its protein level is crucial for maintaining homeostasis. 
      Kelch-like-ECH-associated protein 1 (Keap1) and WD40 repeat protein 23 (WDR23) 
      directly regulate Nrf2 levels via similar but distinct proteasome-dependent 
      pathways. WDR23 forms a part of the WDR23-Cullin 4A-RING ubiquitin ligase complex 
      (CRL4A(WDR23)), whereas Keap1 serves as a substrate adaptor for the Cullin 
      3-containing ubiquitin ligase complex. However, the mechanisms underlying 
      crosstalk between these Keap1 and WDR23 pathways for the regulation of Nrf2 
      levels have not been investigated. Here, we showed that knockdown (KD) of Keap1 
      upregulated the expression of Cullin4A (CUL4A) in a specificity protein 1 
      (Sp1)-dependent manner. We also revealed that Sp1 interacted with Keap1, leading 
      to ubiquitination of Sp1. Increases in Sp1 by Keap1 KD triggered Sp1 binding to 
      the fourth Sp1 binding site (Sp1_M4) within the -230/+50 region of the CUL4A 
      gene. We also demonstrated that the overexpression and KD of Sp1 reduced and 
      increased Nrf2 protein levels, respectively. These effects were abrogated by the 
      WDR23 KD, suggesting that Sp1 also regulates Nrf2 levels via the ubiquitin ligase 
      complex CRL4A(WDR23). In conclusion, we discovered Sp1 as a novel substrate of 
      Keap1 and provided evidence that Sp1 regulates the expression of CUL4A. We 
      revealed a novel role for Sp1 in mediating crosstalk between two independent 
      regulators of Nrf2 protein levels.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Siswanto, Ferbian Milas
AU  - Siswanto FM
AD  - Department of Biomedical Chemistry, School of Science and Technology, Kwansei 
      Gakuin University, Sanda, Japan.
FAU - Oguro, Ami
AU  - Oguro A
AD  - Department of Biomedical Chemistry, School of Science and Technology, Kwansei 
      Gakuin University, Sanda, Japan; Program of Biomedical Science, Graduate School 
      of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.
FAU - Imaoka, Susumu
AU  - Imaoka S
AD  - Department of Biomedical Chemistry, School of Science and Technology, Kwansei 
      Gakuin University, Sanda, Japan. Electronic address: imaoka@kwansei.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210423
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (IL17RB protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Sp1 Transcription Factor)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/*metabolism
MH  - Kinetics
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Sp1 Transcription Factor/*metabolism
MH  - Ubiquitin-Protein Ligases/*metabolism
PMC - PMC8141886
OTO - NOTNLM
OT  - Cullin 4A-RING ligase
OT  - Cullin4A
OT  - DNA damage-binding protein 1
OT  - Kelch-like ECH-associated protein 1
OT  - Ring-box 1
OT  - WD40 repeat protein 23
OT  - gene regulation
OT  - nuclear factor 2 (erythroid-derived 2-like factor)
OT  - oxidative stress
OT  - posttranslational regulation
OT  - specificity protein 1
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2021/04/26 06:00
MHDA- 2021/08/20 06:00
PMCR- 2021/04/23
CRDT- 2021/04/25 20:28
PHST- 2021/01/12 00:00 [received]
PHST- 2021/04/14 00:00 [revised]
PHST- 2021/04/21 00:00 [accepted]
PHST- 2021/04/26 06:00 [pubmed]
PHST- 2021/08/20 06:00 [medline]
PHST- 2021/04/25 20:28 [entrez]
PHST- 2021/04/23 00:00 [pmc-release]
AID - S0021-9258(21)00493-2 [pii]
AID - 100704 [pii]
AID - 10.1016/j.jbc.2021.100704 [doi]
PST - ppublish
SO  - J Biol Chem. 2021 Jan-Jun;296:100704. doi: 10.1016/j.jbc.2021.100704. Epub 2021 
      Apr 23.