TRIM44 Promotes Rabies Virus Replication by Autophagy-Dependent Mechanism.

Tripartite motif (TRIM) proteins are a multifunctional E3 ubiquitin ligase family that participates in various cellular processes. Recent studies have shown that TRIM proteins play important roles in regulating host-virus interactions through specific pathways, but their involvement in response to rabies virus (RABV) infection remains poorly understood. Here, we identified that several TRIM proteins are upregulated in mouse neuroblastoma cells (NA) after infection with the rabies virus using RNA-seq sequencing. Among them, TRIM44 was found to regulate RABV replication. This is supported by the observations that downregulation of TRIM44 inhibits RABV replication, while overexpression of TRIM44 promotes RABV replication. Mechanistically, TRIM44-induced RABV replication is brought about by activating autophagy, as inhibition of autophagy with 3-MA attenuates TRIM44-induced RABV replication. Additionally, we found that inhibition of autophagy with rapamycin reverses the TRIM44-knockdown-induced decrease in LC3B expression and autophagosome formation as well as RABV replication. The results suggest that TRIM44 promotes RABV replication by an autophagy-dependent mechanism. Our work identifies TRIM44 as a key host factor for RABV replication, and targeting TRIM44 expression may represent an effective therapeutic strategy.

Oleocanthal Protects C2C12 Myotubes against the Pro-Catabolic and Anti-Myogenic Action of Stimuli Able to Induce Muscle Wasting In Vivo.

Oleocanthal (OC) is a monophenol of extra-virgin olive oil (EVOO) endowed with antibiotic, cardioprotective and anticancer effects, among others, mainly in view of its antioxidant and anti-inflammatory properties. OC has been largely investigated in terms of its anticancer activity, in Alzheimer disease and in collagen-induced arthritis; however, the possibility that it can also affect muscle biology has been totally overlooked so far. This study is the first to describe that OC modulates alterations induced in C2C12 myotubes by stimuli known to induce muscle wasting in vivo, namely TNF-α, or in the medium conditioned by the C26 cachexia-inducing tumor (CM-C26). C2C12 myotubes were exposed to CM-C26 or TNF-α in the presence or absence of OC for 24 and 48 h and analyzed by immunofluorescence and Western blotting. In combination with TNF-α or CM-C26, OC was revealed to be able to restore both the myotube's original size and morphology and normal levels of both atrogin-1 and MuRF1. OC seems unable to impinge on the autophagic-lysosomal proteolytic system or protein synthesis. Modulations towards normal levels of the expression of molecules involved in myogenesis, such as Pax7, myogenin and MyHC, were also observed in the myotube cultures exposed to OC and TNF-α or CM-C26. In conclusion, the data presented here show that OC exerts a protective action in C2C12 myotubes exposed to TNF-α or CM-C26, with mechanisms likely involving the downregulation of ubiquitin-proteasome-dependent proteolysis and the partial relief of myogenic differentiation impairment.

TRIM47-CDO1 axis dictates hepatocellular carcinoma progression by modulating ferroptotic cell death through the ubiquitin‒proteasome system.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, characterized by high morbidity and mortality rates, as well as unfavorable treatment outcomes. Tripartite motif-containing protein 47 (TRIM47) has been implicated in various diseases including tumor progression with the activity of E3 ubiquitin ligase. However, the precise regulatory mechanisms underlying the involvement of TRIM47 in HCC remain largely unexplored. Here, we provide evidence that TRIM47 exhibits heightened expression in tumor tissues, and its expression is in intimate association with clinical staging and patient prognosis. TRIM47 promotes HCC proliferation, migration, and invasion as an oncogene by in vitro gain- and loss-of-function experiments. TRIM47 knockdown results in HCC ferroptosis induction, primarily through CDO1 involvement to regulate GSH synthesis. Subsequent experiments confirm the interaction between TRIM47 and CDO1 dependent on B30.2 domain, wherein TRIM47 facilitates K48-linked ubiquitination, leading to a decrease in CDO1 protein abundance in HCC. Furthermore, CDO1 is able to counteract the promotional effect of TRIM47 on HCC biological functions. Overall, our research provides novel insight into the mechanism of TRIM47 in CDO1-mediated ferroptosis in HCC cells, highlighting its value as a potential target candidate for HCC therapeutic approaches.

Protective role of pretreatment with Anisodamine against sepsis-induced diaphragm atrophy via inhibiting JAK2/STAT3 pathway.

There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis patients' prognoses. Studies have shown that Anisodamine (Anis) can exert antioxidant effects when blows occur. However, the role of Anisodamine in diaphragm atrophy in sepsis patients has not been reported. Therefore, this study investigated the antioxidant effect of Anisodamine in sepsis-induced diaphragm atrophy and its mechanism. We used cecal ligation aspiration (CLP) to establish a mouse septic mode and stimulated the C2C12 myotube model with lipopolysaccharide (LPS). After treatment with Anisodamine, we measured the mice's bodyweight, diaphragm weight, fiber cross-sectional area and the diameter of C2C12 myotubes. The malondialdehyde (MDA) levels in the diaphragm were detected using the oxidative stress kit. The expression of MuRF1, Atrogin1 and JAK2/STAT3 signaling pathway components in the diaphragm and C2C12 myotubes was measured by RT-qPCR and Western blot. The mean fluorescence intensity of ROS in C2C12 myotubes was measured by flow cytometry. Meanwhile, we also measured the levels of Drp1 and Cytochrome C (Cyt-C) in vivo and in vitro by Western blot. Our study revealed that Anisodamine alleviated the reduction in diaphragmatic mass and the loss of diaphragmatic fiber cross-sectional area and attenuated the atrophy of the C2C12 myotubes by inhibiting the expression of E3 ubiquitin ligases. In addition, we observed that Anisodamine inhibited the JAK2/STAT3 signaling pathway and protects mitochondrial function. In conclusion, Anisodamine alleviates sepsis-induced diaphragm atrophy, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway.

Suppression of AGRN enhances CD8+ T cell recruitment and inhibits breast cancer progression.

Breast cancer (BC) stands as a prominent contributor to global cancer-related mortality, with an increasing incidence annually. This study aims to investigate AGRN gene expression in BC, as well as explore its influence on the tumor immune microenvironment. AGRN displayed a pronounced upregulation in BC tissues relative to paracancerous tissues. Single-cell RNA analysis highlighted AGRN-specific elevation within cancer cell clusters and also showed expression expressed in stromal as well as immune cell clusters. AGRN upregulation was positively correlated with clinicopathological stage and negatively correlated with BC prognosis. As revealed by the in vitro experiment, AGRN knockdown effectively hinders BC cells in terms of proliferation, invasion as well as migration. AGRN protein, which may interact with EXT1, LRP4, RAPSN, etc., was primarily distributed in the cell cytoplasm. Notably, immune factors might interact with AGRN in BC, evidenced by its discernible associations with immunofactors like IL10, CD274, and PVRL2. Mass spectrometry and immunohistochemistry revealed that the reduction of AGRN led to an increase in CD8+ T cells with triple-negative breast cancer (TNBC). Mechanistically, the connection between TRIM7 and PD-L1 is improved by AGRN, acting as a scaffold, thereby facilitating the accelerated degradation of PD-L1 by TRIM7. Downregulation of AGRN inhibits BC progression and increases CD8+ T cell recruitment. Targeting AGRN may contribute to BC treatment. The biomarker AGRN, serving as a therapeutic target for BC, emerges as a prospective avenue for enhancing both diagnosis and prognosis in BC cases.

Inhibition of Immunoproteasome Attenuates NLRP3 Inflammasome Response by Regulating E3 Ubiquitin Ligase TRIM31.

Excessive secretion of pro-inflammatory cytokines leads to the disruption of intestinal barrier in inflammatory bowel disease (IBD). The inflammatory cytokine tumor necrosis factor alpha (TNFα) induces the assembly of the NLRP3 inflammasome, resulting in the augmented secretion of inflammatory cytokines implicated in the pathogenesis of inflammatory bowel disease (IBD). TNFα has also been known to induce the formation of immunoproteasome (IP), which incorporates immunosubunits LMP2, LMP7, and MECL-1. Inhibition of IP activity using the IP subunit LMP2-specific inhibitor YU102, a peptide epoxyketone, decreased the protein levels of NLRP3 and increased the K48-linked polyubiquitination levels of NLRP3 in TNFα-stimulated intestinal epithelial cells. We observed that inhibition of IP activity caused an increase in the protein level of the ubiquitin E3 ligase, tripartite motif-containing protein 31 (TRIM31). TRIM31 facilitated K48-linked polyubiquitination and proteasomal degradation of NLRP3 with an enhanced interaction between NLRP3 and TRIM31 in intestinal epithelial cells. In addition, IP inhibition using YU102 ameliorated the symptoms of colitis in the model mice inflicted with dextran sodium sulfate (DSS). Administration of YU102 in the DSS-treated colitis model mice caused suppression of the NLRP3 protein levels and accompanied inflammatory cytokine release in the intestinal epithelium. Taken together, we demonstrated that inhibiting IP under inflammatory conditions induces E3 ligase TRIM31-mediated NLRP3 degradation, leading to attenuation of the NLRP3 inflammatory response that triggers disruption of intestinal barrier.

NFKBIZ regulates NFκB signaling pathway to mediate tumorigenesis and metastasis of hepatocellular carcinoma by direct interaction with TRIM16.

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and mortality rates. NFKBIZ, a member of the nuclear factor kappa B inhibitory family, is closely related to tumor progression. However, the precise role of NFKBIZ in HCC remains unclear. To explore this, we conducted a series of experiments from clinic to cells. Western blot and qPCR revealed a significant downregulation of NFKBIZ in human HCC tissues. Clinical character analysis showed that the patients with lower NFKBIZ expression had poorer prognosis and higher clinical stage. By using CCK-8, wound healing, transwell invasion and migration assay, we discovered that NFKBIZ expression was reversely associated with the proliferation, invasion, and migration ability of HCC cells in vitro. Additionally, the results obtained from xenograft assay and lung metastasis models showed that NFKBIZ overexpression inhibited the growth and metastasis of HCC cells in vivo. Western blot and immunofluorescence assay further revealed that NFKBIZ mediated HCC cell growth and migration by regulating NFκB signaling transduction. Finally, flow cytometry, protein degradation assay and Co-immunoprecipitation indicated that TRIM16 can enhance NFKBIZ ubiquitination by direct interactions at its K48 site, which may thereby alleviate HCC cell apoptosis to induce the insensitivity to sorafenib. In conclusion, our study demonstrated that NFKBIZ regulated HCC tumorigenesis and metastasis by mediating NFκB signal transduction and TRIM16/NFKBIZ/NFκB axis may be the underlying mechanism of sorafenib insensitivity in HCC.

TRIM27-Induced Protective Autophagy: A Novel Therapeutic Approach for Pneumonia.

BACKGROUND: Pneumonia is a prevalent respiratory ailment involving complex physiological and pathological mechanisms. The tripartite motif containing 27 (TRIM27) plays a crucial role in regulating inflammation mechanisms. Therefore, the purpose of this study is to further explore the therapeutic potential of TRIM27 in pneumonia, based on its regulatory mechanisms in inflammation and autophagy. METHODS: This study established a mouse pneumonia animal model through lipopolysaccharide (LPS) administration, designating it as the LPS model group. Subsequently, adenovirus-mediated TRIM27 overexpression was implemented in the animals of the LPS model group, creating the TRIM27 treatment group. After a 7-day treatment period, lung tissues from the mice were collected. Various techniques, including immunohistochemistry, quantitative reverse transcription PCR (RT-qPCR), western blot, enzyme-linked immunosorbent assay (ELISA), and electron microscopy were utilized to analyze the impact of TRIM27 overexpression on inflammatory factors, oxidative stress, autophagy, and inflammatory processes in pulmonary tissues. Finally, an in vitro LPS cell model was established, and the effects of TRIM27 overexpression and autophagy inhibition on inflammatory cytokines and autophagosomes in LPS-induced inflammatory cells were examined through RT-qPCR and immunofluorescence techniques. RESULTS: The research findings demonstrate a significant reduction in the elevated levels of interleukin-6 (IL-6), IL-1ß, and Tumor necrosis factor-alpha (TNF-α) induced by LPS with TRIM27 overexpression (p < 0.01). Conversely, the autophagy inhibitor 3-Methyladenine (3-MA) diminished the effects induced by TRIM27 overexpression. Moreover, TRIM27 overexpression enhanced the expression of Microtubule-associated protein 1A/1B light chain 3 (LC3) II/I and Beclin-1 proteins in mice subjected to LPS stimulation (p < 0.01), while reducing the expression of the p62 protein (p < 0.01). The addition of 3-MA, however, decreased Beclin-1 expression and inhibited autophagy (p < 0.01). Additionally, TRIM27 overexpression decreased the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cleaved caspase-1, IL-1ß, and Gasdermin D N-terminal fragment (GSDMD-N) proteins in LPS-stimulated mice (p < 0.05). TRIM27 overexpression also decreased the levels of malondialdehyde (MDA), Activating Transcription Factor 6 (ATF6), and C/EBP-homologous protein (CHOP), while increasing the levels of superoxide dismutase (SOD) and glutathione (GSH) in mice exposed to LPS (p < 0.01). CONCLUSION: The induction of TRIM27 overexpression emerges as a potential and effective pneumonia treatment. The underlying mechanism may involve inducing protective autophagy, thereby reducing oxidative stress and cell pyroptosis.

Aminophylline Improves Ventilator-Induced Diaphragmatic Dysfunction by Targeting IGF-1-FOXO1-MURF1 Pathway.

BACKGROUND: The usage of life-saving mechanical ventilation (MV) could cause ventilator-induced diaphragmatic dysfunction (VIDD), increasing both mortality and morbidity. Aminophylline (AP) has the potential to enhance the contractility of animal skeletal muscle fibers and improve the activity of human respiratory muscles, and the insulin-like growth factor-1 (IGF-1)- forkhead box protein O1 (FOXO1)-muscle RING finger-1 (MURF1) pathway plays a crucial role in skeletal muscle dysfunction. This study aimed to investigate the impact of AP on VIDD and to elucidate the role of the IGF-1-FOXO1-MURF1 pathway as an underlying mechanism. METHODS: Rat models of VIDD were established through MV treatment. IGF-1 lentiviral (LV) interference (LV-IGF-1-shRNA; controlled by lentiviral negative control LV-NC) was employed to inhibit IGF-1 expression and thereby block the IGF-1-FOXO1-MURF1 pathway. Protein and mRNA levels of IGF-1, FOXO1, and MURF1 were assessed using western blot and real-time reverse transcriptase-polymerase chain reaction (RT-qPCR), respectively. Diaphragm contractility and morphometry were examined through measurement of compound muscle action potentials (CMAPs) and hematoxylin and eosin (H&E) staining. Oxidative stress was evaluated by levels of hydrogen peroxide (H2O2), superoxide dismutase (SOD), antioxidant glutathione (GSH), and carbonylated protein. Mitochondrial stability was assessed by measuring the mitochondrial membrane potential (MMP), and mitochondrial fission and mitophagy were examined through protein levels of dynamin-related protein 1 (DRP1), mitofusin 2 protein (MFN2), phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), and Parkin (western blot). Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate (UTP) nick-end labeling (TUNEL) assay and levels of Bax, B-cell lymphoma 2 (BCL-2), and Caspase-3. Levels of Atrogin-1, neuronally expressed developmentally downregulated 4 (NEDD4), and muscle ubiquitin ligase of SCF complex in atrophy-1 (MUSA1) mRNA, as well as ubiquitinated protein, were utilized to determine protein degradation. Furthermore, the SUnSET (surface sensing of translation) method was employed to determine rates of protein synthesis. RESULTS: MV treatment upregulated IGF-1 while downregulated FOXO1 and MURF1 (p < 0.05). AP administration reversed IGF-1, FOXO1 and MURF1 (p < 0.05), which was suppressed again by IGF-1 inhibition (p < 0.05), demonstrating the blockage of the IGF-1-FOXO1-MURF1 pathway. MV treatment caused decreased CMAP and cross-sectional areas of diaphragm muscle fibers, and increased time course of CMAP (p < 0.05). Additionally, oxidative stress, cell apoptosis, and protein degradation were increased and mitochondrial stability was decreased by MV treatment (p < 0.05). Conversely, AP administration reversed all these changes induced by MV, but this reversal was disrupted by the blockage of the IGF-1-FOXO1-MURF1 pathway. CONCLUSIONS: In this study, MV treatment induced symptoms of VIDD in rats, which were all effectively reversed by AP regulating the IGF-1-FOXO1-MURF1 pathway, demonstrating the potential of AP in ameliorating VIDD.

Association of the TRIM family protein with survival outcomes and clinicopathological features in colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: The tripartite motif (TRIM) proteins have been reported to play crucial roles in various malignancies. However, the clinical significance of TRIM proteins in colorectal cancer (CRC) remains controversial. This study aimed to evaluate the association between TRIM proteins and the clinicopathological features and survival outcomes in patients with CRC. METHODS: We performed a meta-analysis to investigate whether TRIM is a prognostic factor in CRC. PubMed, Embase, Web of Science, CNKI and Weipu databases were searched to identify eligible studies that evaluated the association between TRIM proteins and overall survival (OS), as well as the clinicopathological features of patients with CRC. Hazard ratios (HR) or odds ratios (OR) with 95% confidence interval (CI) were derived and pooled using a fixed-effects model. RESULTS: From inception to March 2023, we extracted study characteristics and prognostic data for each identified study. Twelve studies enrolling 1608 patients were eligible for inclusion. Data on OS and recurrence-free survival (RFS) were available for 12 and 2 studies, respectively. The pooled analysis results showed a significant correlation between the elevated TRIM proteins and shorter OS (HR = 2.42, 95% CI: 1.96-2.99) and worse RFS (HR = 2.51, 95% CI: 1.78-3.54) in patients with CRC. The combined ORs indicated that TRIM protein over-expression was significantly associated with advanced TNM stage (OR = 2.26, 95% CI: 1.25-4.10), deep tumor invasion (OR = 2.01, 95% CI: 1.04-3.88), lymph node metastasis (OR = 2.99, 95% CI: 2.19-4.09) and perineural invasion (OR = 1.95, 95% CI: 1.18-3.23). CONCLUSIONS: Our findings suggest that TRIM proteins can predict tumor progression and poor prognosis in CRC. Therefore, TRIM proteins may be promising therapeutic targets for patients with CRC.

The E3 ligase TRIM7 suppresses the tumorigenesis of gastric cancer by targeting SLC7A11.

Tripartite motif-containing protein 7 (TRIM7), as an E3 ligase, plays an important regulatory role in various physiological and pathological processes. However, the role of TRIM7 in gastric cancer (GC) is still undefined. Our study detected the expression of TRIM7 in clinical specimens and investigated the regulatory effect and molecular mechanism of TRIM7 on GC progression through in vitro and in vivo experiments. Our finding showed that TRIM7 was significantly downregulated in GC, and patients with high expression of TRIM7 showed long overall survival. Both in vitro and in vivo experiments showed that TRIM7 dramatically suppressed the malignant progression of GC. Further investigation showed that ferroptosis was the major death type mediated by TRIM7. Mechanistically, TRIM7 interacted with SLC7A11 through its B30.2/SPRY domain and promoted Lys48-linked polyubiquitination of SLC7A11, which effectively suppressing SLC7A11/GPX4 axis and inducing ferroptosis in GC cells. In vivo experiments and correlation analysis based on clinical specimens further confirmed that TRIM7 inhibited tumor growth through suppressing SLC7A11/GPX4 axis. In conclusion, our investigation demonstrated for the first time that TRIM7, as a tumor suppressor, induced ferroptosis via targeting SLC7A11 in GC, which provided a new strategy for the molecular therapy of GC by upregulating TRIM7.

Housekeeping U1 snRNA facilitates antiviral innate immunity by promoting TRIM25-mediated RIG-I activation.

U1 small nuclear RNA (snRNA) is an abundant and evolutionarily conserved 164-nucleotide RNA species that functions in pre-mRNA splicing, and it is considered to be a housekeeping non-coding RNA. However, the role of U1 snRNA in regulating host antiviral immunity remains largely unexplored. Here, we find that RNVU1-18, a U1 pseudogene, is significantly upregulated in the host infected with RNA viruses, including influenza and respiratory syncytial virus. Overexpression of U1 snRNA protects cells against RNA viruses, while knockdown of U1 snRNA leads to more viral burden in vitro and in vivo. Knockout of RNVU1-18 is sufficient to impair the type I interferon-dependent antiviral innate immunity. U1 snRNA is required to fully activate the retinoic acid-inducible gene I (RIG-I)-dependent antiviral signaling, since it interacts with tripartite motif 25 (TRIM25) and enhances the RIG-I-TRIM25 interaction to trigger K63-linked ubiquitination of RIG-I. Our study reveals the important role of housekeeping U1 snRNA in regulating host antiviral innate immunity and restricting RNA virus infection.

Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Tripartite motif family - its role in tumor progression and therapy resistance: a review.

PURPOSE OF REVIEW: In this review, we summarized published articles on the role of tripartite motif (TRIM) family members in the initiation and development of human malignancies. RECENT FINDINGS: The ubiquitin-proteasome system (UP-S) plays a critical role in cellular activities, and UP-S dysregulation contributes to tumorigenesis. One of the key regulators of the UP-S is the tripartite motif TRIM protein family, most of which are active E3 ubiquitin ligases. TRIM proteins are critical for the biological functions of cancer cells, including migration, invasion, metastasis, and therapy resistance. Therefore, it is important to understand how TRIM proteins function at the molecular level in cancer cells. SUMMARY: We provide a comprehensive and up-to-date overview about the role TRIMs play in cancer progression and therapy resistance. We propose TRIM family members as potential new markers and targets to overcome therapy failure.

TRIM6 facilitates SARS-CoV-2 proliferation by catalyzing the K29-typed ubiquitination of NP to enhance the ability to bind viral genomes.

The Nucleocapsid Protein (NP) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is not only the core structural protein required for viral packaging, but also participates in the regulation of viral replication, and its post-translational modifications such as phosphorylation have been shown to be an important strategy for regulating virus proliferation. Our previous work identified NP could be ubiquitinated, as confirmed by two independent studies. But the function of NP ubiquitination is currently unknown. In this study, we first pinpointed TRIM6 as the E3 ubiquitin ligase responsible for NP ubiquitination, binding to NP's CTD via its RING and B-box-CCD domains. TRIM6 promotes the K29-typed polyubiquitination of NP at K102, K347, and K361 residues, increasing its binding to viral genomic RNA. Consistently, functional experiments such as the use of the reverse genetic tool trVLP model and gene knockout of TRIM6 further confirmed that blocking the ubiquitination of NP by TRIM6 significantly inhibited the proliferation of SARS-CoV-2. Notably, the NP of coronavirus is relatively conserved, and the NP of SARS-CoV can also be ubiquitinated by TRIM6, indicating that NP could be a broad-spectrum anti-coronavirus target. These findings shed light on the intricate interaction between SARS-CoV-2 and the host, potentially opening new opportunities for COVID-19 therapeutic development.

TRIM5 as a promising diagnostic biomarker of hepatocellular carcinoma: integrated analysis and experimental validation.

The TRIM family is associated with the membrane, and its involvement in the progression, growth, and development of various cancer types has been researched extensively. However, the role played by the TRIM5 gene within this family has yet to be explored to a great extent in terms of hepatocellular carcinoma (HCC). The data of patients relating to mRNA expression and the survival rate of individuals diagnosed with HCC were extracted from The Cancer Genome Atlas (TCGA) database. UALCAN was employed to examine the potential link between TRIM5 expression and clinicopathological characteristics. In addition, enrichment analysis of differentially expressed genes (DEGs) was conducted as a means of deciphering the function and mechanism of TRIM5 in HCC. The data in the TCGA and TIMER2.0 databases was utilized to explore the correlation between TRIM5 and immune infiltration in HCC. WGCNA was performed as a means of assessing TRIM5-related co-expressed genes. The "OncoPredict" R package was also used for investigating the association between TRIM5 and drug sensitivity. Finally, qRT-PCR, Western blotting (WB) and immunohistochemistry (IHC) were employed for exploring the differential expression of TRIM5 and its clinical relevance in HCC. According to the results that were obtained from the vitro experiments, mRNA and protein levels of TRIM5 demonstrated a significant upregulation in HCC tissues. It is notable that TRIM5 expression levels were found to have a strong association with the infiltration of diverse immune cells and displayed a positive correlation with several immune checkpoint inhibitors. The TRIM5 expression also displayed promising clinical prognostic value for HCC patients.

Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans.

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

SP140 inhibitor suppressing TRIM22 expression regulates glioma progress through PI3K/AKT signaling pathway.

BACKGROUND: SP gene family, consisting of SP100, SP110, SP140, and SP140L, has been implicated in the initiation and advancement of numerous malignancies. Nevertheless, their clinical significance in glioma remains incompletely understood. METHOD: Expression levels and prognostic significance of SP family members were evaluated in the TCGA and CGGA datasets. Multifactorial analysis was used to identify SP gene family members that can independently impact the prognosis of glioma patients. A SP140-based predictive risk model/nomogram was developed in TCGA dataset and validated in CGGA dataset. The model's performance was evaluated through receiver operating characteristic (ROC) curves, calibration plots, and decision curve analyses. Phenotypic associations of SP140 and TRIM22 were examined through CancerSEA and TIMER. The effect of SP140 inhibitor in glioma progress and TRIM22/PI3K/AKT signaling pathway was confirmed in U251/U87 glioma cells. RESULTS: The SP family members exhibited elevated expression in gliomas and were negatively correlated with prognosis. SP140 emerged as an independent prognostic factor, and a SP140-based nomogram/predictive risk model demonstrated high accuracy. SP140 inhibitor, GSK761, lead to the suppression of TRIM22 expression and the PI3K/AKT signaling pathway. GSK761 also restrain glioma proliferation, migration, and invasion. Furthermore, SP140 and TRIM22 coexpressed in glioma cells with high level of vascular proliferation, TRIM22 is closely associated with the immune cell infiltration. CONCLUSION: SP140-based nomogram proved to be a practical tool for predicting the survival of glioma patients. SP140 inhibitor could suppress glioma progress via TRIM22/PI3K/AKT signaling pathway.

Advances in the antitumor mechanisms of tripartite motif-containing protein 3.

The tripartite motif-containing (TRIM) protein family has steadily become a hotspot in tumor-related research. As a member of the E3 ubiquitin ligase family, TRIM is working on many crucial biological processes, including the regulation of tumor cell proliferation, metastasis, apoptosis, and autophagy. Among the diverse TRIM superfamily members, TRIM3 operates via different mechanisms in various types of tumors. This review primarily focuses on the current state of research regarding the antitumor mechanisms of TRIM3 in different cancers. A more in-depth study of TRIM3 may provide new directions for future antitumor treatments. Our review focuses on TRIM3 proteins and cancer. We searched for relevant articles on the mechanisms by which TRIM3 affects tumorigenesis and development from 1997 to 2023 and summarized the latest progress and future directions. Triad-containing motif protein 3 (TRIM3) is an important protein, which plays a key role in the process of tumorigenesis and development. The comprehensive exploration of TRIM3 is anticipated to pave the way for future advancements in antitumor therapy, which is expected to be a new hallmark for cancer detection and a novel target for drug action. TRIM3 is poised to become a significant milestone in cancer detection and a promising focal point for drug intervention. Recent years have witnessed notable progress in research aimed at unraveling the antitumor mechanism of TRIM3, with far-reaching implications for practical tumor diagnosis, treatment protocols, efficacy evaluation, economics, and pharmaceutical utilization.

Integrated Multiomics Reveals Silencing of has_circ_0006646 Promotes TRIM21-Mediated NCL Ubiquitination to Inhibit Hepatocellular Carcinoma Metastasis.

Recent studies suggest that circular RNA (circRNA)-mediated post-translational modification of RNA-binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi-omics approach. Has_circ_0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif-containing 21 to reduce the proteasome-mediated degradation of NCL via K48-linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient-derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi-omics landscape of circRNA-mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target.