trim33

The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling...

In mice, exit from the totipotent two-cell (2C) stage embryo requires silencing of the 2C-associated transcriptional program. However, the molecular mechanisms involved in this process remain poorly understood. Here we demonstrate that the 2C-specific transcription factor double homeobox protein (DUX) mediates an essential negative feedback loop by inducing the expression of DUXBL to promote this silencing. We show that DUXBL gains accessibility to DUX-bound regions specifically upon DUX expression. Furthermore, we determine that DUXBL interacts with TRIM24 and TRIM33, members of the TRIM superfamily involved in gene silencing, and colocalizes with them in nuclear foci upon DUX expression...

Estrogen receptor alpha (ER)-positive breast cancer is responsible for over 60% of breast cancer cases in the U.S. Among patients diagnosed with early-stage ER+ disease, 1/3 will experience recurrence despite treatment with adjuvant endocrine therapy. ER is a nuclear hormone receptor responsible for estrogen-driven tumor growth. ER transcriptional activity is modulated by interactions with coregulators. Dysregulation of the levels of these coregulators is involved in the development of endocrine resistance...

The p90 ribosomal S6 kinases (RSK) family of serine/threonine kinases comprises four isoforms (RSK1-4) that lie downstream of the ERK1/2 mitogen-activated protein kinase (MAPK) pathway. RSKs are implicated in fine tuning of cellular processes such as translation, transcription, proliferation, and motility. Previous work showed that pathogens such as Cardioviruses could hijack any of the four RSK isoforms to inhibit PKR activation or to disrupt cellular nucleocytoplasmic trafficking. In contrast, some reports suggest non-redundant functions for distinct RSK isoforms, whereas Coffin-Lowry syndrome has only been associated with mutations in the gene encoding RSK2...

Lysine-based post-translational modification (PTM) such as acylation, acetylation, deamination, methylation, SUMOylation, and ubiquitination has proven to be a major regulator of gene expression, chromatin structure, protein stability, protein-protein interaction, protein degradation, and cellular localization. However, besides all the PTMs, ubiquitination stands as the second most common PTM after phosphorylation that is involved in the etiology of neurodegenerative diseases (NDDs) namely, Alzheimer's disease (AD) and Parkinson's disease (PD)...

Tripartite motif containing 33 (TRIM33) has been reported to be involved in various tumor progression. However, its role in endometrial carcinoma (EC) remains to be elucidated. By mining the publicly available databases UALCAN and TIMER, low expression of TRIM33 was found in tumor tissues of EC patients. Clinically, downregulation of TRIM33 in EC tissues was positively correlated with the extensive muscle invasion and poor differentiation grade. In vitro , experiments performed on human HEC‑1‑A and AN3CA cells showed that overexpression of TRIM33 inhibited the proliferation, migration and invasion of EC cells, whereas TRIM33 knockdown resulted in the opposite results...

PKM2 mediates the Warburg effects and is crucial for tumorigenesis, but its role in hyperplastic skin disorders remains elusive. In this study, we investigated the function of PKM2 in psoriatic keratinocytes. We found that PKM2 expression and its nuclear translocation were induced in the epidermis of psoriasis patients, contributing to aerobic glycolysis and cell growth. Moreover, mass spectrometry combined with immunoprecipitation analysis revealed that PKM2 could interact with TRIM33, an E3 ubiquitin ligase in the nucleus, and this interaction is critical for the nuclear retention of PKM2...

Replicative stress promotes genomic instability and tumorigenesis but also presents an effective therapeutic endpoint, rationalizing detailed analysis of pathways that control DNA replication. We show here that the transcription factor E2f4 recruits the DNA helicase Recql to facilitate progression of DNA replication forks upon drug- or oncogene-induced replicative stress. In unperturbed cells, the Trim33 ubiquitin ligase targets E2f4 for degradation, limiting its genomic binding and interactions with Recql...

Ubiquitination is a reversible process that not only controls protein synthesis and degradation, but also is essential for protein transport, localization and biological activity. Deubiquitinating enzyme (DUB) dysfunction leads to various diseases, including cancer. In this study, we aimed to explore the functions and mechanisms of crucial DUBs in head and neck squamous cell carcinoma (HNSCC). Based on bioinformatic analysis and immunohistochemistry detection, YOD1 was identified to be significantly downregulated in HNSCC specimens compared with adjacent normal tissues...

SUMO modifications regulate the function of many proteins and are important in controlling herpesvirus infections. We performed a site-specific proteomic analysis of SUMO1- and SUMO2-modified proteins in Epstein-Barr virus (EBV) latent and lytic infection to identify proteins that change in SUMO modification status in response to EBV reactivation. Major changes were identified in all three components of the TRIM24/TRIM28/TRIM33 complex, with TRIM24 being rapidly degraded and TRIM33 being phosphorylated and SUMOylated in response to EBV lytic infection...

INTRODUCTION: Although targeted therapies have revolutionized the therapeutic landscape of lung adenocarcinomas (LUADs), disease progression on single-agent targeted therapy against known oncogenic drivers is common, and therapeutic options after disease progression are limited. In patients with MDM2 amplification (MDM2amp) and a concurrent oncogenic driver alteration, we hypothesized that targeting of the tumor-suppressor pathway (by means of restoration of p53 using MDM2 inhibition) and simultaneous targeting of co-occurring MAPK oncogenic pathway might represent a more durably effective therapeutic strategy...

Patients with metastatic pancreatic cancer have limited treatment options and a dismal prognosis. While RET fusion is rare (0.6%) in pancreatic cancer, the efficacy of RET-targeted treatment in patients with TRIM33-RET fusion has not been previously reported. Herein, we presented a case of a 68-year-old man with pancreatic cancer harboring TRIM33-RET fusion who responded remarkably to pralsetinib despite being intolerant to chemotherapy. To our knowledge, this is the first report on the clinical value of a single TRIM33-RET fusion in pancreatic cancer, which may benefit from the targeted therapy...

The long interspersed element 1 (LINE-1 or L1) integration is affected by many cellular factors through various mechanisms. Some of these factors are required for L1 amplification, while others either suppress or enhance specific steps during L1 propagation. Previously, TRIM28 has been identified to suppress transposable elements, including L1 expression via its canonical role in chromatin remodeling. Here, we report that TRIM28 through its B box domain increases L1 retrotransposition and facilitates shorter cDNA and L1 insert generation in cultured cells...

OBJECTIVE: To compare the ultrasonography and pathology features between children and adolescents with papillary thyroid carcinoma (PTC). METHODS: A total of 53 patients who were surgically diagnosed with childhood or adolescent PTC between 2017 and 2022 were included in this study. The pre-operative ultrasonography, post-operative histology, and molecular and clinical characteristics were retrospectively analyzed. RESULTS: No differences were observed in composition, echogenicity, and shape using ultrasonography...

Triphenyltin (TPT) is widely distributed on coastlines, which makes coral reef fish a potential target of TPT pollution. However, the negative effects of TPT on coral reef fish remain poorly understood. Therefore, in the present study, the larval coral reef fish Amphiprion ocellaris was used to investigate the developmental toxicities of TPT at environmentally relevant concentrations (0, 1, 10 and 100 ng/L). After TPT exposure for 14 d, the cumulative mortality increased, and growth was suppressed. In addition, TPT exposure inhibited the development of melanophores and xanthophores and delayed white strip formation, which might be responsible for the disruption of the genes (erbb3b, mitfa, kit, xdh, tyr, oca2, itk and trim33) related to pigmentation...

TRIM33 is a chromatin reader required for mammalian mesendoderm differentiation after activation of Nodal signaling, while its role in mESCs is still elusive. Here, we report that TRIM33 co-localizes with promyelocytic leukemia nuclear bodies (PML-NBs) specifically in mESCs, to mediate Nodal signaling-directed transcription of Lefty1/2. We show that TRIM33 puncta formation in mESCs depends on PML and on specific assembly of PML-NBs. Moreover, TRIM33 and PML co-regulate Lefty1/2 expression in mESCs, with both PML protein and formation of mESCs-specific PML-NBs being required for TRIM33 recruitment to these loci, and PML-NBs directly associating with the Lefty1/2 loci...

With the increasing use of next-generation sequencing, highly effective targeted therapies have been emerging as treatment options for several cancer types. Recurrent gene-fusions have been recognized in sarcomas; however, options for targeted therapy remain scarce. Here, we describe a case of a sarcoma, associated with a RET::TRIM33-fusion gene with an exceptional response to a neoadjuvant therapy with the selective RET inhibitor selpercatinib. Resected tumor revealed subtotal histopathologic response. This is the first report of successful targeted therapy with selpercatinib in RET-fusion-associated sarcomas...

The field of targeted protein degradation, through the control of the ubiquitin-proteasome system (UPS), is progressing considerably; to exploit this new therapeutic modality, the proteolysis targeting chimera (PROTAC) technology was born. The opportunity to use PROTACs engaging of new E3 ligases that can hijack and control the UPS system could greatly extend the applicability of degrading molecules. To this end, here we show a potential application of the ELIOT (E3 LIgase pocketOme navigaTor) platform, previously published by this group, for a scaffold-repurposing strategy to identify new ligands for a novel E3 ligase, such as TRIM33...

Alpha-herpesvirus causes lifelong infections and serious diseases in a wide range of hosts and has developed multiple strategies to counteract the host defense. Here, we demonstrate that the tegument protein UL21 (unique long region 21) in pseudorabies virus (PRV) dampens type I interferon signaling by triggering the degradation of CGAS (cyclic GMP-AMP synthase) through the macroautophagy/autophagy-lysosome pathway. Mechanistically, the UL21 protein scaffolds the E3 ligase UBE3C (ubiquitin protein ligase E3C) to catalyze the K27-linked ubiquitination of CGAS at Lys384, which is recognized by the cargo receptor TOLLIP (toll interacting protein) and degraded in the lysosome...

BACKGROUND: Rheumatoid arthritis (RA) can cause irreversible joint injury and serious disability. This study aimed to investigate how TRIM33 regulated by KLF9 affects the aggressive behaviors of synovial fibroblasts induced by tumor necrosis factor-α (TNF-α). MATERIALS AND METHODS: TNF-α-induced MH7A cells were used to simulate the in vitro model of RA. TRIM33 and KLF9 expression in TNF-α-challenged MH7A cells and transfection efficiency were analyzed via real-time reverse transcription polymerase chain reaction together with western blot...