{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRIM9 is a brain‐specific E3 ubiquitin ligase that is predominantly expressed in cortical neurons, where it regulates neuronal function and homeostasis. In the healthy brain, TRIM9 participates in protein ubiquitination events that modulate synaptic and axonal processes; for example, it ubiquitinates the netrin‐1 receptor DCC to control FAK activation and thereby influences axon branching. In addition, TRIM9 expression is notably altered in neurodegenerative conditions – its levels are diminished in affected brain regions of patients with Parkinson’s disease and Lewy body dementia, while TRIM9 accumulates in Lewy bodies. TRIM9 is also induced in peri‐infarct areas following ischemic stroke, where by sequestering components of the SCF ubiquitin‐ligase complex it limits IκBα degradation and the ensuing NF‐κB–mediated neuroinflammatory response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in neuronal integrity, TRIM9 also functions as a key regulator of inflammatory and antiviral signaling. A brain‐selective activity of TRIM9 involves its interaction with β‐TrCP that prevents the proteasomal degradation of IκBα and precursor p100, thereby acting as a negative modulator of NF‐κB activation and pro‐inflammatory cytokine production. In contrast, the short isoform TRIM9s is induced upon viral infection, undergoing K63‐linked auto‐polyubiquitination to serve as a molecular platform that bridges GSK3β to TBK1, which enhances IRF3 activation and selectively boosts type I interferon responses while curbing excessive inflammation. Moreover, TRIM9s facilitates p38 signaling by stabilizing MKK6 through K63‐linked ubiquitination, a mechanism that contributes to tumor suppression in glioblastoma. In other systems, such as in irinotecan‐induced intestinal mucositis, elevated TRIM9 exacerbates barrier dysfunction and inflammation via p38 pathway activation, with knockdown of TRIM9 mitigating these deleterious effects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also points to roles for TRIM9 in tumorigenesis and tumor progression. Studies in uterine leiomyoma, non‐small cell lung cancer, and esophageal cancer suggest that aberrations in the TRIM9 regulatory network may serve as diagnostic markers and potential therapeutic targets in these malignancies, implicating TRIM9 in the modulation of cancer‐associated signaling pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kunikazu Tanji, Tetsu Kamitani, Fumiaki Mori, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM9, a novel brain-specific E3 ubiquitin ligase, is repressed in the brain of Parkinson's disease and dementia with Lewy bodies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurobiol Dis (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nbd.2010.01.007"}], "href": "https://doi.org/10.1016/j.nbd.2010.01.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20085810"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20085810"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Melissa Plooster, Shalini Menon, Cortney C Winkle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.E16-08-0594"}], "href": "https://doi.org/10.1091/mbc.E16-08-0594"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28701345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28701345"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jianxiong Zeng, Yaoming Wang, Zhifei Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.12.055"}], "href": "https://doi.org/10.1016/j.celrep.2018.12.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30970257"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30970257"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mude Shi, Hyelim Cho, Kyung-Soo Inn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Negative regulation of NF-κB activity by brain-specific TRIpartite Motif protein 9."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms5820"}], "href": "https://doi.org/10.1038/ncomms5820"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25190485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25190485"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yunfei Qin, Qingxiang Liu, Shuo Tian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM9 short isoform preferentially promotes DNA and RNA virus-induced production of type I interferon by recruiting GSK3β to TBK1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2016.27"}], "href": "https://doi.org/10.1038/cr.2016.27"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26915459"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26915459"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Kunpeng Liu, Chuanxia Zhang, Bowen Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.03.096"}], "href": "https://doi.org/10.1016/j.celrep.2018.03.096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29669288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29669288"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Wenjun Zhao, Qingming Wang "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of TRIM9 attenuates irinotecan‑induced intestinal mucositis in IEC‑6 cells by regulating DUSP6 expression via the P38 pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2021.12507"}], "href": "https://doi.org/10.3892/mmr.2021.12507"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34676875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34676875"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Fang Yang, Hong Liu, Yonghui Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM9 overexpression promotes uterine leiomyoma cell proliferation and inhibits cell apoptosis via NF-κB signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Life Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.lfs.2020.118101"}], "href": "https://doi.org/10.1016/j.lfs.2020.118101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32679146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32679146"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Zunqiao Wang, Bin Wang, Keping Wang "}, {"type": "b", "children": [{"type": "t", "text": "Targeting TRIM9 by miR-218-5p Restricts Cell Proliferation and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Clin Lab Sci (2023)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36889762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36889762"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zhaoxian Lin, Jianyuan Huang, Lihuan Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM9 Interacts with ZEB1 to Suppress Esophageal Cancer by Promoting ZEB1 Protein Degradation via the UPP Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Res Int (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2023/2942402"}], "href": "https://doi.org/10.1155/2023/2942402"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37124931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37124931"}]}]}]}