TNF-α-induced E3 ligase, TRIM15 inhibits TNF-α-regulated NF-κB pathway by promoting turnover of K63 linked ubiquitination of TAK1

Roy, Milton; Singh, Kritarth; Shinde, Anjali; Singh, Jyoti; Mane, Minal; Bedekar, Sawani; Tailor, Yamini; Gohel, Dhruv; Vasiyani, Hitesh; Currim, Fatema

doi:10.1016/j.cellsig.2021.110210

Cited by 12 publications

(9 citation statements)

References 51 publications

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“…HSPA1A and HSPA1B are heat shock proteins that regulate the secretion of TNF-α, IL-1β and IL-10 from monocytes ( 133 ). TRIM15, on the other hand, stimulates TNF-α and is involved in the TNF-α/NF-κB pathway, contributing to the inflammatory response ( 91 ). In the present study psoriasis was associated with SNPs in TNF (rs1800629) and TNIP1 (rs76956521, rs2233278, rs75851973 and rs8177833).…”

Section: Discussionmentioning

confidence: 99%

Genome‑wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan

Yang,

Liu,

et al. 2024

Mol Med Rep

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Psoriasis is a chronic inflammatory dermatological disease, and there is a lack of understanding of the genetic factors involved in psoriasis in Taiwan. To establish associations between genetic variations and psoriasis, a genome-wide association study was performed in a cohort of 2,248 individuals with psoriasis and 67,440 individuals without psoriasis. Using the ingenuity pathway analysis software, biological networks were constructed. Human leukocyte antigen (HLA) diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)-R software and chi-square analysis. The present study aimed to assess the potential risks associated with psoriasis using a polygenic risk score (PRS) analysis. The genetic association between single nucleotide polymorphisms (SNPs) in psoriasis and various human diseases was assessed by phenome-wide association study. METAL software was used to analyze datasets from China Medical University Hospital (CMUH) and BioBank Japan (BBJ). The results of the present study revealed 8,585 SNPs with a significance threshold of P<5×10 −8 , located within 153 genes strongly associated with the psoriasis phenotype, particularly on chromosomes 5 and 6. This specific genomic region has been identified by analyzing the biological networks associated with numerous pathways, including immune responses and inflammatory signaling. HLA genotype analysis indicated a strong association between HLA-A*02:07 and HLA-C*06:02 in a Taiwanese population. Based on our PRS analysis, the risk of psoriasis associated with the SNPs identified in the present study was quantified. These SNPs are associated with various dermatological, circulatory, endocrine, metabolic, musculoskeletal, hematopoietic and infectious diseases. The meta-analysis results indicated successful replication of a study conducted on psoriasis in the BBJ. Several genetic loci are significantly associated with susceptibility to psoriasis in Taiwanese individuals. The present study contributes to our understanding of the genetic determinants that play a role in susceptibility to psoriasis. Furthermore, it provides valuable insights into the underlying etiology of psoriasis in the Taiwanese community.

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Section: Discussionmentioning

confidence: 99%

Genome‑wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan

Yang,

Liu,

et al. 2024

Mol Med Rep

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“…TRIM15 is dysregulated in tumor cells and associated with tumorigenesis. TRIM15 is a TNF-α-induced E3 ligase [ 40 ]. Here, we showed that TKI treatment inhibited AKT signaling, which enhanced the binding of FOXO1 to the promoter region of TRIM15 .…”

Section: Discussionmentioning

confidence: 99%

“…Liang et al reported that TRIM15 directly targets Keap1 for degradation [ 12 ]. In addition to enhancing the degradation of its substrates, TRIM15 has also been reported to mediate K63-linked ubiquitination of its substrates, such as TAK1 [ 40 ] and ERK1/2 [ 24 ], and modulate the function of these proteins. Similarly, we demonstrated that TRIM15 promoted K63-linked ubiquitination of LASP1 to regulate the subcellular localization of LASP1 in HCC cells.…”

Section: Discussionmentioning

confidence: 99%

TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs

et al. 2023

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For patients with advanced or metastatic Hepatocellular carcinoma (HCC) who are not suitable for surgical resection, systemic therapy has been considered to be the standard treatment. In recent years, a small subset of patients with unresectable HCC have been benefit from tyrosine kinase inhibitors (TKIs), and the overall survival time of these patients is significantly increased. However, all responders ultimately develop resistance to TKI treatment. The tripartite motif (TRIM) family member TRIM15 acts as an E3 ligase to mediate the polyubiquitination of substrates in cells. However, the biological role of TRIM15 in HCC is still an enigma. In our study, our results demonstrated that TRIM15 was abnormally upregulated in liver cancer cells after treated with TKIs and that this upregulation of TRIM15 contributed to TKI resistance in liver cancer cells. Then, we demonstrated that the upregulation of TRIM15 after TKI treatment was mediated by the AKT/FOXO1 axis. Moreover, we demonstrated that TRIM15 induced the nuclear translocation of LASP1 by mediating its K63-linked polyubiquitination, which modulated sensitivity to TKIs by increasing the phosphorylation of AKT and the expression of Snail in liver cancer cells. Collectively, we identified a novel AKT/FOXO1/TRIM15/LASP1 loop in cells, which provided potential candidates for overcoming TKI resistance in HCC.

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“…Yim et al found that RANKL treatment induced the expression of USP18 in preosteoclast cells, and depletion of USP18 increased RANKL‐mediated osteoclastogenesis, although the mechanism remains unclear 126 . TAK1‐mediated activation of NF‐κB signalling has been shown to require K63‐linked ubiquitination of TAK1 127,128 . USP18 can cleave the TAK1 K63‐linked polyubiquitin chain 34,129 and downregulate TAK1‐regulated NF‐κB signalling in BMMs, 129 which may explain the reason that USP18 deficiency increases RANKL‐mediated osteoclastogenesis.…”

Section: Effects Of Usps On Osteoclastogenesis and Bone Resorptionmentioning

confidence: 99%

Ubiquitin‐specific peptidases: Players in bone metabolism

et al. 2023

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Osteoporosis is an ageing‐related disease, that has become a major public health problem and its pathogenesis has not yet been fully elucidated. Substantial evidence suggests a strong link between overall age‐related disease progression and epigenetic modifications throughout the life cycle. As an important epigenetic modification, ubiquitination is extensively involved in various physiological processes, and its role in bone metabolism has attracted increasing attention. Ubiquitination can be reversed by deubiquitinases, which counteract protein ubiquitination degradation. As the largest and most structurally diverse cysteinase family of deubiquitinating enzymes, ubiquitin‐specific proteases (USPs), comprising the largest and most structurally diverse cysteine kinase family of deubiquitinating enzymes, have been found to be important players in maintaining the balance between bone formation and resorption. The aim of this review is to explore recent findings highlighting the regulatory functions of USPs in bone metabolism and provide insight into the molecular mechanisms governing their actions during bone loss. An in‐deep understanding of USPs‐mediated regulation of bone formation and bone resorption will provide a scientific rationale for the discovery and development of novel USP‐targeted therapeutic strategies for osteoporosis.

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TNF-α-induced E3 ligase, TRIM15 inhibits TNF-α-regulated NF-κB pathway by promoting turnover of K63 linked ubiquitination of TAK1

Cited by 12 publications

References 51 publications

Genome‑wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan

Genome‑wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan

TRIM15 forms a regulatory loop with the AKT/FOXO1 axis and LASP1 to modulate the sensitivity of HCC cells to TKIs

Ubiquitin‐specific peptidases: Players in bone metabolism

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