PRMT6-mediated ADMA promotes p62 phase separation to form a negative feedback loop in ferroptosis
These videos have been matched automatically. Contact us if they are not relevant.
These videos have been matched automatically. Contact us if they are not relevant.
View abstract on PubMed
Summary
This summary is machine-generated.Targeting PRMT6-mediated p62 modification enhances ferroptosis by inhibiting the Nrf2 pathway. This discovery offers a new strategy to sensitize cancer cells to ferroptosis-activating therapies.
Area Of Science
- Molecular Biology
- Cancer Research
- Cell Death Mechanisms
Background
- Ferroptosis-activating therapies face limitations due to intrinsic cellular defense mechanisms.
- The p62-Keap1-Nrf2 axis forms a negative feedback loop during ferroptosis, but p62 activation remains unclear.
Purpose Of The Study
- To elucidate the mechanism of p62 activation during ferroptosis induction.
- To investigate the role of p62 in the ferroptosis defense pathway.
- To explore targeting strategies for enhancing ferroptosis in cancer treatment.
Main Methods
- Cell viability assays (MTS), lipid ROS detection (C11-BODIPY), qPCR, and Western blotting were used.
- Immunofluorescence, FRAP, IP, co-IP, and PLA were employed to study protein interactions and modifications.
- In vivo tumor xenograft models assessed the efficacy in pancreatic cancer.
Main Results
- Nrf2 and its downstream genes were upregulated upon ferroptosis induction.
- p62 and PRMT6 (Protein arginine methyltransferase 6) mediated p62 phase separation and body formation by ADMA (asymmetric dimethylarginine) modification, sequestering Keap1 and activating Nrf2.
- Knockdown of p62 or PRMT6 sensitized pancreatic cancer cells to ferroptosis in vitro and in vivo.
Conclusions
- PRMT6-mediated p62 ADMA promotes phase separation, sequesters Keap1, activates Nrf2 signaling, and inhibits ferroptosis.
- Targeting PRMT6-mediated p62 ADMA represents a novel therapeutic strategy to enhance ferroptosis sensitivity in cancer.
These videos have been matched automatically. Contact us if they are not relevant.
These videos have been matched automatically. Contact us if they are not relevant.
Related Concept Videos
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...