TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers

Gong, Jun; Liu, Yuhui; Wang, Wenjia; He, Ruizhi; Xia, Qilong; Chen, Lin; Zhao, Chunle; Gao, Yang; Shi, Yongkang; Bai, Yu; Liao, Yangwei; Zhang, Qi; Zhu, Feng; Wang, Min; Li, Xu; Qin, Renyi

doi:10.1002/advs.202302318

Cited by 15 publications

(8 citation statements)

References 67 publications

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“…There was one previous study with ndings similar to ours showing that the E3 ubiquitin ligase TRIM21 binds to FSP1 and facilitates its ubiquitination, which is crucial for the membrane translocation of FSP1 and its ability to suppress ferroptosis in multiple gastrointestinal (GI) tumors 13 . This means that ubiquitination of FSP1 proteins is a critical requirement for their function.…”

Section: Discussionsupporting

confidence: 67%

RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis

Ma,

Xie,

Wang

et al. 2023

Preprint

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Medulloblastoma (MB) is a prevalent malignant brain tumor among children, which can be classified into four primary molecular subgroups. Group 3 MB (G3-MB) is known to be highly aggressive and associated with a poor prognosis, necessitating the development of novel and effective therapeutic interventions. Ferroptosis, a regulated form of cell death induced by lipid peroxidation, has been identified as a natural tumor suppression mechanism in various cancers. Nevertheless, the potential role of ferroptosis in the treatment of G3-MB remains unexplored. In this study, we demonstrate that RNF126 acts as an anti-ferroptotic gene by interacting with ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) and ubiquitinating FSP1 at the 4KR-2 sites. Additionally, the deletion of RNF126 reduces the subcellular localization of FSP1 in the plasma membrane, resulting in an increase in the CoQ/CoQH2 ratio in G3-MB. The RNF126-FSP1-CoQ10 pathway plays a pivotal role in suppressing phospholipid peroxidation and ferroptosis both in vivo and in vitro. Our findings indicate that RNF126 regulates G3-MB sensitivity to ferroptosis by ubiquitinating FSP1, which provides new evidence for the potential G3-MB therapy.

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Section: Discussionsupporting

confidence: 67%

RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis

Ma,

Xie,

Wang

et al. 2023

Preprint

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“…4J ). To determine the specific binding sequence, a series of TNKS1BP1, TRIM21, and CNOT4 truncation mutants were constructed according to previous studies [ 23 , 30 , 31 ] for co-IP analysis (Fig. 4K ).…”

Section: Resultsmentioning

confidence: 99%

TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion

Wang,

Sandrine,

et al. 2024

Cell Death Dis

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Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, tankyrasel binding protein 1 (TNKS1BP1) was found to interact with tripartite motif containing 21 (TRIM21) and mediated the ubiquitination of CCR4-NOT transcription complex subunit 4 (CNOT4) at the K239 residue via K48 and K6 linkage, which was essential for its tumorigenesis function. Autophagy and lipid reprogramming were identified as two possible mechanisms underlying the pro-tumor effect of TNKS1BP1. Upregulated TNKS1BP1 inhibited autophagy while induced lipid accumulation by inhibiting the JAK2/STAT3 pathway upon the degradation of CNOT4 in HCC. Importantly, knocking down TNKS1BP1 synergized with anti-PD-L1 treatment by upregulating PD-L1 expression on tumor cells via the JAK2/STAT3 pathway, and remodeling the tumor microenvironment by increasing infiltration of tumor-infiltrating lymphocytes as well as augmenting the effect of cytotoxic T lymphocytes. In conclusion, this study identified TNKS1BP1 as a predictive biomarker for patient prognosis and a promising therapeutic target to overcome anti-PD-L1 resistance in HCC.

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“…33,41 Yuan et al 42 identified YTH N6-methyladenosine RNA binding protein C1 (YTHDC1) as a tumor progressive suppressor through the modulation of FSP1 mRNA stability. Additionally, Gong et al 43 found that tripartite motif containing 21 (TRIM21) binds to FSP1 and mediates its ubiquitination on K322 and K366 residues through K63 linkage in gastrointestinal tumors, leading to tumor progression. However, despite the critical role of FSP1, limited FSP1 inhibitors have been identified so far, with iFSP1 being the most popular one.…”

Section: Discussionmentioning

confidence: 99%

The crystal structure of human ferroptosis suppressive protein 1 in complex with flavin adenine dinucleotide and nicotinamide adenine nucleotide

Feng,

Huang,

Tang

et al. 2024

MedComm

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Ferroptosis is a recently discovered form of regulated cell death characterized by its distinct dependence on iron and the peroxidation of lipids within cellular membranes. Ferroptosis plays a crucial role in physiological and pathological situations and has attracted the attention of numerous scientists. Ferroptosis suppressive protein 1 (FSP1) is one of the main regulators that negatively regulates ferroptosis through the GPX4‐independent FSP1–CoQ10–NAD(P)H axis and is a potential therapeutic target for ferroptosis‐related diseases. However, the crystal structure of FSP1 has not been resolved, which hinders the development of therapeutic strategies targeting FSP1. To unravel this puzzle, we purified the human FSP1 (hFSP1) protein using the baculovirus eukaryotic cell expression system and solved its crystal structure at a resolution of 1.75 Å. Furthermore, we evaluated the oxidoreductase activity of hFSP1 with NADH as the substrate and identified E156 as the key amino acid in maintaining hFSP1 activity. Interestingly, our results indicated that hFSP1 exists and functions in a monomeric state. Mutagenesis analysis revealed the critical role of the C‐terminal domain in the binding of substrate. These findings significantly enhance our understanding of the functional mechanism of FSP1 and provide a precise model for further drug development.

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TRIM21‐Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers

Cited by 15 publications

References 67 publications

RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis

RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis

TNKS1BP1 facilitates ubiquitination of CNOT4 by TRIM21 to promote hepatocellular carcinoma progression and immune evasion

The crystal structure of human ferroptosis suppressive protein 1 in complex with flavin adenine dinucleotide and nicotinamide adenine nucleotide

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