Tripartite Motif Protein Research Articles

TRIM29 in Cutaneous Squamous Cell Carcinoma.

Tripartite motif (TRIM) proteins play important roles in a wide range of cell physiological processes, such as signal transduction, transcriptional regulation, innate immunity, and programmed cell death. TRIM29 protein, encoded by the ATDC gene, belongs to the RING-less group of TRIM protein family members. It consists of four zinc finger motifs in a B-box domain and a coiled-coil domain, and makes use of the B-box domain as E3 ubiquitin ligase in place of the RING. TRIM29 was found to be involved in the formation of homodimers and heterodimers in relation to DNA binding; additional studies have also demonstrated its role in carcinogenesis, DNA damage signaling, and the suppression of radiosensitivity. Recently, we reported that TRIM29 interacts with keratins and FAM83H to regulate keratin distribution. Further, in cutaneous SCC, the expression of TRIM29 is silenced by DNA methylation, leading to the loss of TRIM29 and promotion of keratinocyte migration. This paper reviews the role of TRIM family proteins in malignant tumors, especially the role of TRIM29 in cutaneous SCC.

Genome-Wide Identification and Expression Analysis of Potential Antiviral Tripartite Motif Proteins (TRIMs) in Grass Carp (Ctenopharyngodon idella).

Simple SummaryGrass carp, Ctenopharyngodon idellus, is an important freshwater cultured teleost in China, and its annual production has reached 5,533,083 tons. However, its aquaculture is severely restricted by hemorrhagic disease caused by the grass carp reovirus (GCRV). For the better control of grass carp hemorrhagic disease, the breeding of resistant grass carp strains based on antiviral immune molecule markers is a potential solution. However, the molecular basis of grass carp’s resistance to GCRV infection remains largely unknown, greatly limiting the breeding of grass carp resistant to hemorrhagic disease. Given the importance of tripartite motif proteins (TRIMs) in animal antiviral immunity, we used the Hidden Markov Model Biological Sequence Analysis software (HMMER) and SMART to identify TRIMs in the grass carp genome and analyze their gene loci, as well as structural and evolutionary features. We also tried to uncover antiviral TRIMs and their mediated immune processes based on two sets of transcriptomes during GCRV infection in grass carp. This study provides information for the understanding of TRIMs and antiviral immunity in grass carp.Tripartite motif proteins (TRIMs), especially B30.2 domain-containing TRIMs (TRIMs-B30.2), are increasingly well known for their antiviral immune functions in mammals, while antiviral TRIMs are far from being identified in teleosts. In the present study, we identified a total of 42 CiTRIMs from the genome of grass carp, Ctenopharyngodon idella, an important cultured teleost in China, based on hmmsearch and SMART analysis. Among these CiTRIMs, the gene loci of 37 CiTRIMs were located on different chromosomes and shared gene collinearities with homologous counterparts from human and zebrafish genomes. They possessed intact conserved RBCC or RB domain assemblies at their N-termini and eight different domains, including the B30.2 domain, at their C-termini. A total of 19 TRIMs-B30.2 were identified, and most of them were clustered into a large branch of CiTRIMs in the dendrogram. Tissue expression analysis showed that 42 CiTRIMs were universally expressed in various grass carp tissues. A total of 11 significantly differentially expressed CiTRIMs were found in two sets of grass carp transcriptomes during grass carp reovirus (GCRV) infection. Three of them, including Cibtr40, CiTRIM103 and CiTRIM109, which all belonged to TRIMs-B30.2, were associated with the type I interferon response during GCRV infection by weighted network co-expression and gene expression trend analyses, suggesting their involvement in antiviral immunity. These findings may offer useful information for understanding the structure, evolution, and function of TRIMs in teleosts and provide potential antiviral immune molecule markers for grass carp.

Recurrent expansions of B30.2-associated immune receptor families in fish.

B30.2 domains, also known as PRY/SPRY, are key components of specific subsets of two large families of proteins involved in innate immunity: the tripartite motif proteins (TRIMs) and the Nod-like receptors (NLRs). TRIM proteins are important, often inducible factors of antiviral innate immunity, targeting multiple steps of viral cycles through a variety of mechanisms. NLRs prime and regulate systemic innate defenses, especially against bacteria, and control inflammation. Large TRIM and NLR subsets characterized by the presence of a B30.2 domain have been reported from a few fish species including zebrafish and seem to be strongly prone to gene duplication/expansion. Here, we performed a large-scale survey of these receptors across about 150 fish genomes, focusing on ray-finned fishes. We assessed the number and genomic distribution of domains and domain combinations associated with TRIMs, NLRs, and other genes containing B30.2 domains and looked for gene expansion patterns across fish groups. We then used a model to test the impact of taxonomy, genome size, and environmental variables on the copy numbers of these genes. Our findings reveal novel domain structures, clade-specific gains and losses. They also assist with the timing of the gene expansions, reveal patterns associated with the MHC, and lay the groundwork for further studies delving deeper into the forces that drive the copy number variation of immune genes on a species level.

Downregulation of tripartite motif protein 11 attenuates cardiomyocyte apoptosis after ischemia/reperfusion injury via DUSP1-JNK1/2.

Currently, the prevention of ischemic diseases such as myocardial infarction associated with ischemia/reperfusion (I/R) injury remains to be a challenge. Thus, this study was designed to explore the effects of tripartite motif protein 11 (TRIM11) on cardiomyocytes I/R injury and its underlying mechanism. Cardiomyocytes AC16 were used to establish an I/R injury cell model. After TRIM11 downregulation in I/R cells, cell proliferation (0, 12, 24, and 48 h) and apoptosis at 48 h as well as the related molecular changes in oxidative stress‐related pathways was detected. Further, after the treatment of TRIM11 overexpression, SP600125, or DUSP1 overexpression, cell proliferation, apoptosis, and related genes were detected again. As per our findings, it was determined that TRIM11 was highly expressed in the cardiomyocytes AC16 after I/R injury. Downregulation of TRIM11 was determined to have significantly reduced I/R‐induced proliferation suppression and apoptosis. Besides, I/R‐activated c‐Jun N‐terminal kinase (JNK) signaling and cleaved caspase 3 and Bax expression were significantly inhibited by TRIM11 downregulation. In addition, the overexpression of TRIM11 significantly promoted apoptosis in AC16 cells, and JNK1/2 inhibition and DUSP1 overexpression potently counteracted the induction of TRIM11 overexpression in AC16 cells. These suggested that the downregulation of TRIM11 attenuates apoptosis in AC16 cells after I/R injury probably through the DUSP1‐JNK1/2 pathways.

The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury.

Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms “acute lung injury,” “ubiquitin ligases,” “tripartite motif protein,” “inflammation,” and “ubiquitination” using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.

Severity, Pathogenicity and Transmissibility of Delta and Lambda Variants of SARS-CoV-2, Toxicity of Spike Protein and Possibilities for Future Prevention of COVID-19.

The World Health Organization reports that SARS-CoV-2 has infected over 220 million people and claimed over 4.7 million lives globally. While there are new effective vaccines, the differences in behavior of variants are causing challenges in vaccine development or treatment. Here, we discuss Delta, a variant of concern, and Lambda, a variant of interest. They demonstrate high infectivity and are less responsive to the immune response in vaccinated individuals. In this review, we briefly summarize the reason for infectivity and the severity of the novel variants. Delta and Lambda variants exhibit more changes in NSPs proteins and the S protein, compared to the original Wuhan strain. Lambda also has numerous amino acid substitutions in NSPs and S proteins, plus a deletion in the NTD of S protein, leading to partial escape from neutralizing antibodies (NAbs) in vaccinated individuals. We discuss the role of furin protease and the ACE2 receptor in virus infection, hotspot mutations in the S protein, the toxicity of the S protein and the increased pathogenicity of Delta and Lambda variants. We discuss future therapeutic strategies, including those based on high stability of epitopes, conservation of the N protein and the novel intracellular antibody receptor, tripartite-motif protein 21 (TRIM21) recognized by antibodies against the N protein.

The TRIM proteins in cancer: from expression to emerging regulatory mechanisms.

New clinical evidence suggests that dysregulation of the ubiquitin-mediated destruction of tumor suppressors or oncogene products is probably engaged in the etiology of leukemia and carcinoma. The superfamily of tripartite motif (TRIM)-containing protein family is among the biggest recognized single protein RING finger E3 ubiquitin ligases that are considered vital carcinogenesis regulators, which is not shocking since TRIM proteins are engaged in various biological processes, including cell growth, development, and differentiation; hence, TRIM proteins' alterations may influence apoptosis, cell proliferation, and transcriptional regulation. In this review article, the various mechanisms through which TRIM proteins exert their role in the most prevalent malignancies including lung, prostate, colorectal, liver, breast, brain cancer, and leukemia are summarized.

Tripartite Motif Protein 6 Promotes Colorectal Cancer Cell Migration and Metastasis via SOCS2-STAT3 Signaling.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, with most mortalities being caused by metastases. However, the underlying molecular mechanism of CRC metastases remains largely unknown. Emerging evidence has shown the role of the tripartite motif family, especially tripartite motif protein 6 (TRIM6), in carcinogenesis. In this study, we used CRC cell lines with TRIM6 knockdown and overexpression to investigate the function of TRIM6 in CRC metastasis. We found that TRIM6 promotes CRC cell migration and invasion both in vitro and in vivo. TRIM6 knockdown slows down the migration and invasion processes, whereas TRIM6 overexpression accelerates CRC cell migration and invasion. TRIM6 is potentially the upstream regulatory factor for signal transducer and activator of transcription 3 (STAT3) via the suppressor of cytokine signaling 2 (SOCS2). A total of 70 samples from patients with CRC further confirmed that TRIM6 expression level is positively correlated with STAT3 phosphorylation and negatively correlated with SOCS2 expression. Therefore, TRIM6 could be a potential therapeutic target for CRC metastasis.

TRIM21 regulates pyroptotic cell death by promoting Gasdermin D oligomerization.

Gasdermin-D (GSDMD), the executioner of pyroptotic cell death when it is cleaved by inflammatory caspases, plays a crucial role in host defense and the response to danger signals. So far, there are no known mechanisms, other than cleavage, for regulating GSDMD. Here, we show that tripartite motif protein TRIM21 acts as a positive regulator of GSDMD-dependent pyroptosis. TRIM21 interacted with GSDMD via its PRY-SPRY domain, maintaining GSDMD stable expression in resting cells yet inducing the N-terminus of GSDMD (GSDMD-N) aggregation during pyroptosis. TRIM21-deficient cells displayed a reduced cell death in response to NLRP3 or NLRC4 inflammasome activation. Genetic ablation of TRIM21 in mice conferred protection from LPS-induced inflammation and dextran sulfate sodium-induced colitis. Therefore, TRIM21 plays an essential role in GSDMD-mediated pyroptosis and may be a viable target for controlling and treating inflammation-associated diseases.

SNP rs4971059 predisposes to breast carcinogenesis and chemoresistance via TRIM46-mediated HDAC1 degradation.

Identification of the driving force behind malignant transformation holds the promise to combat the relapse and therapeutic resistance of cancer. We report here that the single nucleotide polymorphism (SNP) rs4971059, one of 65 new breast cancer risk loci identified in a recent genome-wide association study (GWAS), functions as an active enhancer of TRIM46 expression. Recreating the G-to-A polymorphic switch caused by the SNP via CRISPR/Cas9-mediated homologous recombination leads to an overt upregulation of TRIM46. We find that TRIM46 is a ubiquitin ligase that targets histone deacetylase HDAC1 for ubiquitination and degradation and that the TRIM46-HDAC1 axis regulates a panel of genes, including ones critically involved in DNA replication and repair. Consequently, TRIM46 promotes breast cancer cell proliferation and chemoresistance invitro and accelerates tumor growth invivo. Moreover, TRIM46 is frequently overexpressed in breast carcinomas, and its expression is correlated with lower HDAC1 expression, higher histological grades, and worse prognosis of the patients. Together, our study links SNP rs4971059 to replication and to breast carcinogenesis and chemoresistance and support thepursuit of TRIM46 as a potential target for breast cancer intervention.

TRIM47 activates NF-κB signaling via PKC-ε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer

Increasing attention has been paid to roles of tripartite motif-containing (TRIM) family proteins in cancer biology, often functioning as E3 ubiquitin ligases. In the present study, we focus on a contribution of TRIM47 to breast cancer biology, particularly to endocrine therapy resistance, which is a major clinical problem in breast cancer treatment. We performed immunohistochemical analysis of TRIM47 protein expression in 116 clinical samples of breast cancer patients with postoperative endocrine therapy using tamoxifen. Our clinicopathological study showed that higher immunoreactivity scores of TRIM47 were significantly associated with higher relapse rate of breast cancer patients (P = 0.012). As functional analyses, we manipulated TRIM47 expression in estrogen receptor-positive breast cancer cells MCF-7 and its 4-hydroxytamoxifen (OHT)-resistant derivative OHTR, which was established in a long-term culture with OHT. TRIM47 promoted both MCF-7 and OHTR cell proliferation. MCF-7 cells acquired tamoxifen resistance by overexpressing exogenous TRIM47. We found that TRIM47 enhances nuclear factor kappa-B (NF-κB) signaling, which further up-regulates TRIM47. We showed that protein kinase C epsilon (PKC-ε) and protein kinase D3 (PKD3), known as NF-κB-activating protein kinases, are directly associated with TRIM47 and stabilized in the presence of TRIM47. As an underlying mechanism, we showed TRIM47-dependent lysine 27-linked polyubiquitination of PKC-ε. These results indicate that TRIM47 facilitates breast cancer proliferation and endocrine therapy resistance by forming a ternary complex with PKC-ε and PKD3. TRIM47 and its associated kinases can be a potential diagnostic and therapeutic target for breast cancer refractory to endocrine therapy.

TRIM25 and DEAD-Box RNA Helicase DDX3X Cooperate to Regulate RIG-I-Mediated Antiviral Immunity.

The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and -independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEAD-box helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25’s catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-β production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence.

RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment

BackgroundNecroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-κB during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes.MethodsWe employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8+ T cells or dendritic cells (DC) in all TCGA tumors.ResultsWe identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses.ConclusionOur data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity.

TRIM38 protects chondrocytes from IL-1β-induced apoptosis and degeneration via negatively modulating nuclear factor (NF)-κB signaling

Tripartite motif protein 38 (TRIM38) has been documented as a vital modulator of inflammation. However, the relevance of TRIM38 in osteoarthritis is not yet known. In this work, we aimed to explore any possible effects of TRIM38 on interleukin-1β (IL-1β)-stimulated chondrocytes, an in vitro cellular model of osteoarthritis. Analyzing our data showed significant decreases in the levels of TRIM38 in chondrocytes following IL-1β stimulation. Gain-of-function studies revealed that overexpression of TRIM38 markedly increased the viability of IL-1β-stimulated chondrocytes while decreasing their rate of apoptosis and degeneration. Conversely, depletion of TRIM38 enhanced the sensitivity of chondrocytes to IL-1β-induced injury. Further research demonstrated that TRIM38 was capable of inhibiting IL-1β-induced activation of nuclear factor (NF)-κB signaling. Reactivation of NF-κB markedly reversed TRIM38-overexpression-mediated effects, while inhibition of NF-κB significantly abolished TRIM38-depletion-induced effects in IL-1β-stimulated chondrocytes. In summary, the findings of this work suggest that TRIM38 is capable of ameliorating IL-1β-induced apoptosis and degeneration of chondrocytes via suppression of NF-κB signaling. Our work indicates a potential role of TRIM38 in osteoarthritis and proposes it as a new therapeutic target for osteoarthritis.

Genetic analysis of TRIM family genes for early-onset Parkinson's disease in Chinese population

IntroductionAmounting evidence has suggested the Tripartite Motif (TRIM) family proteins as related to Parkinson's disease (PD). However, many of the risk genes were still awaiting further explorations, and their genetic role in PD has not been investigated yet. MethodsHere, we aimed to systematically evaluate the genetic associations of TRIMs with PD in a large Chinese early-onset PD (EOPD, age at onset < 50 years) cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated EOPD patients using whole exome sequencing, and evaluated the association between rare variants and EOPD at allele and gene levels. ResultsTotally 123 rare variants were identified in 13 TRIM protein family members, including TRIM3, TRIM6, TRIM8, TRIM9, TRIM10, TRIM11, TRIM17, TRIM24, TRIM27, TRIM28, TRIM34, TRIM40 and TRIM41. At the allele level, three variants were nominally associated with PD, namely p.R65H in TRIM10, p.P467S in TRIM11, and p.I425V in TRIM24. Gene-based burden analysis showed a clear enrichment of rare variants of TRIM24 in EOPD. ConclusionThese results demonstrate TRIM24 as a potential risk gene for PD, provide a better understanding for the genetic involvement of TRIM protein family members in EOPD and broaden the current mutation spectrum of PD.

TRIM16 overexpression inhibits the metastasis of colorectal cancer through mediating Snail degradation

Tripartite motif containing 16 (TRIM16) is a member of the tripartite motif protein family and functions as a potential tumor suppressor in several cancers. However, the specific function and clinical significance of TRIM16 in colorectal cancer (CRC) remains unclear. In this study, we observed that low TRIM16 expression was detected frequently in primary colorectal cancer (CRC) tissues and was closely associated with a better prognosis. Functional studies demonstrate that TRIM16 overexpression notably inhibits the metastasis abilities of CRC in vivo and in vitro. Mechanistically, our results demonstrated that TRIM16 directly bound and ubiquitinated Snail family transcriptional repressor 1 (Snail), an important transcriptional factor of the epithelial-mesenchymal transition (EMT) process suppressing the EMT in CRC. Additionally, our data revealed that the inhibition effect of TRIM16 on cancer metastasis was dependent on Snail degradation. Collectively, our study is the first to report that TRIM16 plays a crucial anti-tumor role in CRC tumorigenesis. We also provided novel evidence that TRIM16 might act as a prognostic and therapeutic target to assess and inhibit CRC progression.

Impaired TRIM16-Mediated Lysophagy in Chronic Obstructive Pulmonary Disease Pathogenesis.

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Ectopic Expression of TRIM25 Restores RIG-I Expression and IFN Production Reduced by Multiple Enteroviruses 3Cpro.

Enteroviruses (EVs) 3C proteins suppress type I interferon (IFN) responses mediated by retinoid acid-inducible gene I (RIG-I), while an E3 ubiquitin ligase, tripartite motif protein 25 (TRIM25)-mediated RIG-I ubiquitination is essential for RIG-I antiviral activity. Therefore, whether the effect of EVs 3C on RIG-I is associated with TRIM25 expression is worth to be further investigated. Here, we demonstrate that 3C proteins of EV71 and coxsackievirus B3 (CVB3) reduced not only RIG-I expression but also TRIM25 expression through protease cleavage activity, while overexpression of TRIM25 restored RIG-I expression and IFN-β production reduced by 3C proteins. Further investigation confirmed that the two amino acids and functional domains in TRIM25 required for RIG-I ubiquitination and TRIM25 structural conformation were essential for the recovery of RIG-I expression. Moreover, we also observed that TRIM25 could rescue RIG-I expression reduced by 3C proteins of CVA6 and EV-D68 but not CVA16. Our findings provide an insightful interpretation of 3C-mediated host innate immune suppression and support TRIM25 as an attractive target against multiple EVs infection.

TRIMming Down Hormone-Driven Cancers: The Biological Impact of TRIM Proteins on Tumor Development, Progression and Prognostication.

The tripartite motif (TRIM) protein family is attracting increasing interest in oncology. As a protein family based on structure rather than function, a plethora of biological activities are described for TRIM proteins, which are implicated in multiple diseases including cancer. With hormone-driven cancers being among the leading causes of cancer-related death, TRIM proteins have been described to portrait tumor suppressive or oncogenic activities in these tumor types. This review describes the biological impact of TRIM proteins in relation to hormone receptor biology, as well as hormone-independent mechanisms that contribute to tumor cell biology in prostate, breast, ovarian and endometrial cancer. Furthermore, we point out common functions of TRIM proteins throughout the group of hormone-driven cancers. An improved understanding of the biological impact of TRIM proteins in cancer may pave the way for improved prognostication and novel therapeutics, ultimately improving cancer care for patients with hormone-driven cancers.

Identification of a TRIM32 from Penaeus monodon is involved in autophagy and innate immunity during white spot syndrome virus infection

Many tripartite motif (TRIM) family proteins played an important role in regulating innate immune and autophagy pathway and were important for host defenses against viral pathogens. However, the role of TRIM proteins in autophagy and innate immunity during virus infection was seldom studied in crustaceans. In this study, a novel TRIM32 homolog was identified from Penaeus monodon (named PmTRIM32). PmTRIM32 was significantly upregulated by rapamycin stimulation and WSSV infection. RNA interference experiments showed that PmTRIM32 could restrict WSSV replication and lead P. monodon more resistance to WSSV challenge. Autophagy could be induced by WSSV or rapamycin challenge and has been proved to play a positive role in restricting WSSV replication in P. monodon. The autophagy activity induced by WSSV or rapamycin challenge could be obviously inhibited by silence of PmTRIM32 in P. monodon. Further studies revealed that PmTRIM32 positively regulated the expression of nuclear transcription factor (NF-κB) and it mediated antimicrobial peptides. Moreover, Pull-down and in vitro ubiquitination assay demonstrated that PmTRIM32 could interact with WSSV envelope protein and target it for ubiquitination in vitro. Collectively, this study demonstrated that PmTRIM32 restricted WSSV replication and was involved in positively regulating autophagy and NF-κB pathway during WSSV infection in P. monodon.