Ferroptosis Regulator Information

General Information of the Ferroptosis Regulator (ID: REG10369)
Regulator Name Serine/threonine-protein kinase TBK1 (TBK1)
Synonyms
NF-kappa-B-activating kinase
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Gene Name TBK1
Gene ID 29110
Regulator Type Protein coding
Uniprot ID Q9UHD2
Sequence
MQSTSNHLWLLSDILGQGATANVFRGRHKKTGDLFAIKVFNNISFLRPVDVQMREFEVLK
KLNHKNIVKLFAIEEETTTRHKVLIMEFCPCGSLYTVLEEPSNAYGLPESEFLIVLRDVV
GGMNHLRENGIVHRDIKPGNIMRVIGEDGQSVYKLTDFGAARELEDDEQFVSLYGTEEYL
HPDMYERAVLRKDHQKKYGATVDLWSIGVTFYHAATGSLPFRPFEGPRRNKEVMYKIITG
KPSGAISGVQKAENGPIDWSGDMPVSCSLSRGLQVLLTPVLANILEADQEKCWGFDQFFA
ETSDILHRMVIHVFSLQQMTAHKIYIHSYNTATIFHELVYKQTKIISSNQELIYEGRRLV
LEPGRLAQHFPKTTEENPIFVVSREPLNTIGLIYEKISLPKVHPRYDLDGDASMAKAITG
VVCYACRIASTLLLYQELMRKGIRWLIELIKDDYNETVHKKTEVVITLDFCIRNIEKTVK
VYEKLMKINLEAAELGEISDIHTKLLRLSSSQGTIETSLQDIDSRLSPGGSLADAWAHQE
GTHPKDRNVEKLQVLLNCMTEIYYQFKKDKAERRLAYNEEQIHKFDKQKLYYHATKAMTH
FTDECVKKYEAFLNKSEEWIRKMLHLRKQLLSLTNQCFDIEEEVSKYQEYTNELQETLPQ
KMFTASSGIKHTMTPIYPSSNTLVEMTLGMKKLKEEMEGVVKELAENNHILERFGSLTMD
GGLRNVDCL

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Family Ser/Thr protein kinase family
Function
Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X. This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro- inflammatory and antiviral genes including IFNA and IFNB. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1. Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1- containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation. Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes. Phosphorylates and activates AKT1. Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates Borna disease virus (BDV) P protein. Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system.

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HGNC ID
HGNC:11584
KEGG ID hsa:29110
Full List of the Ferroptosis Target of This Regulator and Corresponding Disease/Drug Response(s)
TBK1 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).
Browse Target
Browse Disease
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Nuclear factor erythroid 2-related factor 2 (NFE2L2) [Suppressor; Marker]
 Target Info 
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis Target of This Regulator [1]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Drug Tiliroside Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 106 HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm3, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde.

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Response regulation Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
Hepatocellular carcinoma [ICD-11: 2C12]
 Disease Info 
In total 1 item(s) under this disease
Experiment 1 Reporting the Ferroptosis-centered Disease Response [1]
Target Regulator Serine/threonine-protein kinase TBK1 (TBK1) Protein coding
 Regulator Info 
Responsed Drug Tiliroside Investigative
 Drug Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 106 HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm3, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde.

    Click to Show/Hide
Response regulation Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
Tiliroside [Investigative]
 Drug Info 
In total 1 item(s) under this drug
Experiment 1 Reporting the Ferroptosis-centered Drug Response [1]
Drug for Ferroptosis Inducer
Response Target Nuclear factor erythroid 2-related factor 2 (NFE2L2) Suppressor; Marker
 Target Info 
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model
 Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
All animal studies were approved by the Committee on Ethics of Animal Experiments of Binzhou Medical University (approval no: BZMU-IACUC-2021-331, date: 09/10/2021). To generate the ectopic HCC mouse models, HepG2-luciferase cells (HepG2 cells transfected with luciferase gene) were suspended in serum-free media and matrigel (BD Biosciences) at a ratio of 1:1 v/v. A total of 2.5 x 106 HepG2-luciferase cells/100 ul were injected into the left axilla of mice. After reaching a tumor size of 100-150 mm3, all mice were randomly divided into four groups: control (vehicle, intraperitoneal [i.p.]), tiliroside (20 mg/kg,i.p.), sorafenib (30 mg/kg,i.p.), or combination treatment (tiliroside and sorafenib,i.p.). All treatments were administered every 3 d, and the length and width of tumor were measured every 4 d. The formula tumor volume = (length x width2)/2 was used to calculate the tumor volume. Body weight was recorded every 7 d, and the morphology of the tumor was photographed using animal in vivo imaging technology (IVIS Spectrum; PerkinElmer) before the day of sacrifice. The mice were sacrificed 40 d after administration, and the tumors were dissected and weighed. The major organs and xenograft tumors were fixed with 4% paraformaldehyde.

    Click to Show/Hide
Response regulation Tiliroside directly binds to TBK1 and inhibits its activity, which inhibits the phosphorylation of Ser349 on p62. Consequently, this decreases the affinity of p62 for Keap1, promotes ubiquitination and degradation of Nrf2 and ferroptosis, and eventually increases the sensitivity of hepatocellular carcinoma cells to sorafenib.
References
Ref 1 Tiliroside targets TBK1 to induce ferroptosis and sensitize hepatocellular carcinoma to sorafenib. Phytomedicine. 2023 Mar;111:154668. doi: 10.1016/j.phymed.2023.154668. Epub 2023 Jan 15.