General Information of the Ferroptosis Regulator (ID: REG10113)
Regulator Name E3 ubiquitin-protein ligase TRIM21 (TRIM21)
Synonyms
RNF81, RO52, SSA1; 52 kDa Ro protein; 52 kDa ribonucleoprotein autoantigen Ro/SS-A; RING finger protein 81; RING-type E3 ubiquitin transferase TRIM21; Ro(SS-A); Sjoegren syndrome type A antigen; Tripartite motif-containing protein 21
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Gene Name TRIM21
Gene ID 6737
Regulator Type Protein coding
Uniprot ID P19474
Sequence
MASAARLTMMWEEVTCPICLDPFVEPVSIECGHSFCQECISQVGKGGGSVCPVCRQRFLL
KNLRPNRQLANMVNNLKEISQEAREGTQGERCAVHGERLHLFCEKDGKALCWVCAQSRKH
RDHAMVPLEEAAQEYQEKLQVALGELRRKQELAEKLEVEIAIKRADWKKTVETQKSRIHA
EFVQQKNFLVEEEQRQLQELEKDEREQLRILGEKEAKLAQQSQALQELISELDRRCHSSA
LELLQEVIIVLERSESWNLKDLDITSPELRSVCHVPGLKKMLRTCAVHITLDPDTANPWL
ILSEDRRQVRLGDTQQSIPGNEERFDSYPMVLGAQHFHSGKHYWEVDVTGKEAWDLGVCR
DSVRRKGHFLLSSKSGFWTIWLWNKQKYEAGTYPQTPLHLQVPPCQVGIFLDYEAGMVSF
YNITDHGSLIYSFSECAFTGPLRPFFSPGFNDGGKNTAPLTLCPLNIGSQGSTDY

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Family TRIM/RBCC family
Function
E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B ('Thr-187' phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin- mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Regulates also autophagy through FIP200/RB1CC1 ubiquitination and subsequent decreased protein stability. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses. Represses the innate antiviral response by facilitating the formation of the NMI- IFI35 complex through 'Lys-63'-linked ubiquitination of NMI. During viral infection, promotes cell pyroptosis by mediating 'Lys-6'-linked ubiquitination of ISG12a/IFI27, facilitating its translocation into the mitochondria and subsequent CASP3 activation. When up-regulated through the IFN/JAK/STAT signaling pathway, promotes 'Lys-27'-linked ubiquitination of MAVS, leading to the recruitment of TBK1 and up-regulation of innate immunity.

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HGNC ID
HGNC:11312
KEGG ID hsa:6737
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
TRIM21 can regulate the following target(s), and cause disease/drug response(s). You can browse detail information of target(s) or disease/drug response(s).
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Phospholipid hydroperoxide glutathione peroxidase (GPX4) [Suppressor]
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Suppressor
Responsed Disease Acute kidney failure ICD-11: GB60
Responsed Drug Fedratinib Investigative
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Mice were fasted for 12 h and anesthetized (1% pentobarbital sodium, i.p.) before surgery. Bilateral renal pedicles were clamped for 30 min, then remove the arterial clamps. The sham groups were treated in the same way, except for the clamping of the renal pedicle. Blood samples were collected 24 h after reperfusion, mice were killed, and kidney were collected for follow-up experiments. Fedratinib (5 mg/kg body weight) was injected (i.p.) into mice 24 h once in advance before surgery.

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Response regulation A JAK2 inhibitor Fedratinib downregulated TRIM21 expression and reduced damage both in vivo and in vitro, which is correlated with the upregulation of GPX4. Our study showed that loss of TRIM21 could alleviate ferroptosis induced by I/R, revealed the mechanism of ubiquitination degradation of GPX4 by TRIM21 and suggested TRIM21 is a potential target for the treatment of acute kidney injury (AKI).
Acute kidney failure [ICD-11: GB60]
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator E3 ubiquitin-protein ligase TRIM21 (TRIM21) Protein coding
Responsed Drug Fedratinib Investigative
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Mice were fasted for 12 h and anesthetized (1% pentobarbital sodium, i.p.) before surgery. Bilateral renal pedicles were clamped for 30 min, then remove the arterial clamps. The sham groups were treated in the same way, except for the clamping of the renal pedicle. Blood samples were collected 24 h after reperfusion, mice were killed, and kidney were collected for follow-up experiments. Fedratinib (5 mg/kg body weight) was injected (i.p.) into mice 24 h once in advance before surgery.

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Response regulation A JAK2 inhibitor Fedratinib downregulated TRIM21 expression and reduced damage both in vivo and in vitro, which is correlated with the upregulation of GPX4. Our study showed that loss of TRIM21 could alleviate ferroptosis induced by I/R, revealed the mechanism of ubiquitination degradation of GPX4 by TRIM21 and suggested TRIM21 is a potential target for the treatment of acute kidney injury (AKI).
Fedratinib [Investigative]
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Suppressor
Response Target Phospholipid hydroperoxide glutathione peroxidase (GPX4) Suppressor
Responsed Disease Acute kidney failure ICD-11: GB60
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model
HK-2 cells Normal Homo sapiens CVCL_0302
In Vivo Model
Mice were fasted for 12 h and anesthetized (1% pentobarbital sodium, i.p.) before surgery. Bilateral renal pedicles were clamped for 30 min, then remove the arterial clamps. The sham groups were treated in the same way, except for the clamping of the renal pedicle. Blood samples were collected 24 h after reperfusion, mice were killed, and kidney were collected for follow-up experiments. Fedratinib (5 mg/kg body weight) was injected (i.p.) into mice 24 h once in advance before surgery.

    Click to Show/Hide
Response regulation A JAK2 inhibitor Fedratinib downregulated TRIM21 expression and reduced damage both in vivo and in vitro, which is correlated with the upregulation of GPX4. Our study showed that loss of TRIM21 could alleviate ferroptosis induced by I/R, revealed the mechanism of ubiquitination degradation of GPX4 by TRIM21 and suggested TRIM21 is a potential target for the treatment of acute kidney injury (AKI).
References
Ref 1 TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury. Life Sci. 2023 May 15;321:121608. doi: 10.1016/j.lfs.2023.121608. Epub 2023 Mar 21.