PMID- 37961303
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231114
DP  - 2023 Oct 27
TI  - Regulation of NRF2 by Phosphoinositides and Small Heat Shock Proteins.
LID - 2023.10.26.564194 [pii]
LID - 10.1101/2023.10.26.564194 [doi]
AB  - Reactive oxygen species (ROS) are generated by aerobic metabolism, and their 
      deleterious effects are buffered by the cellular antioxidant response, which 
      prevents oxidative stress. The nuclear factor erythroid 2-related factor 2 (NRF2) 
      is a master transcriptional regulator of the antioxidant response. Basal levels 
      of NRF2 are kept low by ubiquitin-dependent degradation of NRF2 by E3 ligases, 
      including the Kelch-like ECH-associated protein 1 (KEAP1). Here, we show that the 
      stability and function of NRF2 is regulated by the type I phosphatidylinositol 
      phosphate kinase g (PIPKIg), which binds NRF2 and transfers its product 
      phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P (2) ) to NRF2. PtdIns(4,5)P 
      (2) binding recruits the small heat shock protein HSP27 to the complex. Silencing 
      PIPKIg or HSP27 destabilizes NRF2, reduces expression of its target gene HO-1, 
      and sensitizes cells to oxidative stress. These data demonstrate an unexpected 
      role of phosphoinositides and HSP27 in regulating NRF2 and point to PIPKIg and 
      HSP27 as drug targets to destabilize NRF2 in cancer. IN BRIEF: Phosphoinositides 
      are coupled to NRF2 by PIPKIgamma, and HSP27 is recruited and stabilizes NRF2, 
      promoting stress-resistance.
FAU - Chen, Changliang
AU  - Chen C
FAU - Chen, Mo
AU  - Chen M
FAU - Wen, Tianmu
AU  - Wen T
FAU - Anderson, Richard A
AU  - Anderson RA
FAU - Cryns, Vincent L
AU  - Cryns VL
LA  - eng
PT  - Preprint
DEP - 20231027
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10634847
EDAT- 2023/11/14 06:43
MHDA- 2023/11/14 06:44
PMCR- 2023/11/09
CRDT- 2023/11/14 03:55
PHST- 2023/11/14 06:44 [medline]
PHST- 2023/11/14 06:43 [pubmed]
PHST- 2023/11/14 03:55 [entrez]
PHST- 2023/11/09 00:00 [pmc-release]
AID - 2023.10.26.564194 [pii]
AID - 10.1101/2023.10.26.564194 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Oct 27:2023.10.26.564194. doi: 
      10.1101/2023.10.26.564194.