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Last update 08 May 2025

TRIM15

Last update 08 May 2025

Basic Info

Synonyms

RING finger protein 93, RNF93, TRIM15

+ [6]

Introduction

E3 ubiquitin ligase that plays a role in several processes including innate antiviral immnity, cell migration and chemotaxis (PubMed:23077300, PubMed:34142270). Acts as a 'Lys-63'-specific ubiquitin ligase for MAPK1/ERK2 and MAPK3/ERK1, promoting their activation by facilitating their interaction with MAP2K1 and MAP2K2 (PubMed:34497368). Plays also a role in cell migration and chemotaxis by acting as a stable focal adhesion component upon recruitment by multi-adapter protein paxillin/PXN (PubMed:25015296). Functions in the RIGI-mediated interferon induction pathway upstream or at the level of MAVS (PubMed:23077300). Inhibits NF-kappa-B activation by turnover of 'Lys-63'-linked ubiquitination of MAP3K7/TAK1. Mechanistically, prevents TRIM8 cytoplasmic translocation and thus inhibits TRIM8-mediated 'Lys-63'-linked polyubiquitination of MAP3K7/TAK1 in the cytoplasm (PubMed:34871740). Plays also an important regulatory effect on the activation of hepatic stellate cells (HSCs).

Drugs associated with TRIM15

AAV5-TRIM15 shRNA

Target

TRIM15

Mechanism

TRIM15 inhibitors

Active Org.

Southeast University Affiliated Zhonda Hospital

Originator Org.

Southeast University Affiliated Zhonda Hospital

Active Indication

Osteoarthritis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CN117431208

Patent Mining

Target

TRIM15

Mechanism-

Active Org.

Nanchang University

Originator Org.

Nanchang University

Active Indication

Immune System Diseases [+2]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TRIM15

100 Translational Medicine associated with TRIM15

0 Patents (Medical) associated with TRIM15

Literatures (Medical) associated with TRIM15

15 Jun 2025·International Journal of Cancer

Hypoxia‐mediated high expression of TRIM15 promotes malignant progression of high‐grade serous ovarian cancer through activation of AKT signaling pathway by K63 ubiquitination

Article

Author: Kang, Fuli ; Wei, Heng ; Tan, Shuang ; Lin, Lin ; Li, Yibing ; Lu, Xiaohang ; Zhang, Yang ; Huang, Jiazhen ; Wang, Ning ; Wei, Wei

AbstractThe tripartite motif (TRIM) family member TRIM15 is an E3 ubiquitin ligase that is abnormally expressed in a variety of tumors, but its role and mechanism in high‐grade serous ovarian cancer (HGSOC) are unclear. Here, we found for the first time that TRIM15 was upregulated in HGSOC and was associated with poor overall survival. Functional experiments showed that TRIM15 drove the proliferation of HGSOC cells and inhibited the apoptosis of tumor cells in vivo and in vitro. In terms of mechanism, we found that TRIM15 contributed to the malignant proliferation of HGSOC cells by promoting the activation of AKT and that there was a direct binding between them. TRIM15 induced lysine‐63 (K63) ubiquitination of AKT through its Ring domain, which in turn activated the AKT signaling pathway. In addition, TRIM15‐mediated K63 ubiquitination occurs mainly in the pleckstrin homology (PH) domain of AKT. We further identified other proteins and their functions regulated by TRIM15 in HGSOC cells by ubiquitin proteomic analysis. Furthermore, hypoxia‐inducible factor‐1α promoted TRIM15 transcriptional activation by binding to the hypoxia response elements of the TRIM15 promoter. Our study suggests that TRIM15 induces K63 ubiquitination of the AKT PH domain through its Ring domain and activates the AKT signaling pathway, thereby promoting HGSOC progression. In addition, the abnormally high expression of TRIM15 was associated with the hypoxic microenvironment of HGSOC tissues.

26 Mar 2025·Science Translational Medicine

TRIM15 drives chondrocyte senescence and osteoarthritis progression

Article

Author: Ji, Ming-liang ; Hu, Xinyue ; Li, Zhuang ; Zhang, Weituo ; Lu, Jun ; Wei, Xiao ying ; Shen, Shuying ; Hu, Jun zheng ; Liu, Haoyang

Osteoarthritis (OA) is a prevalent joint disease characterized by pain, disability, and loss of physical function, posing a challenge to public health. However, molecular mechanisms of OA pathogenesis have not been fully described. We report that tripartite motif containing 15 (TRIM15) is a regulator in chondrocyte senescence and OA. Our study revealed heightened expression of TRIM15 in chondrocytes of senescent cartilage from patients with OA and in aged wild-type mice. Using gain- and loss-of-function studies, we found that TRIM15 facilitated human chondrocyte senescence. Conditional deletion of Trim15 in mouse chondrocytes severely impaired skeletal growth, partially because of impaired embryonic chondrocyte senescence. Compared with conditionally knocked out Col2a1-CreER T2 /Trim15 flox/flox mice, Trim15flox/flox control mice exhibited accelerated OA phenotypes, increased senescence markers, and senescence-associated secretory phenotype during aging. Mechanistically, TRIM15 bound with yes-associated protein (YAP) and mediated K48-linked YAP ubiquitination at K254, which interrupted the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. Dysregulation of TRIM15-YAP and transcriptional coactivator with PDZ-binding motif (TAZ) signaling promoted OA progression in both the surgery-induced and natural aging–induced mouse OA model. Intra-articular injection of adeno-associated virus 5 (AAV5)– Trim15 shRNA decelerated OA progression in mice. In particular, YAP and TAZ protein amounts were increased in chondrocytes of patients with OA. Our preclinical results demonstrated that the AAV5- TRIM15 shRNA treatment protected human OA explants against degeneration through inhibiting chondrocyte senescence. Together, our findings underscore the potential of targeting TRIM15 in reshaping the aging cartilage microenvironment and suggest a promising therapeutic avenue for OA.

01 Jun 2024·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis

Article

Author: Guo, Feng ; Wu, Heshui ; Yin, Shilin ; Cai, Hongkun ; Zhao, Jingyuan ; Ren, Dianyun ; Li, Dan ; Wu, Heyu ; Zhou, Yingke ; Xia, Wentao ; Zhang, Qiyue ; Sun, Yan ; Liang, Xueyi ; Qin, Gengdu ; Qin, Yang ; Zhao, Yuhan

BACKGROUNDThe tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive.METHODSWe used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo.RESULTSTRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15.CONCLUSIONSTRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

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TRIM15

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