PDLIM2 suppresses human T-cell leukemia virus type I Tax-mediated tumorigenesis by targeting Tax into the nuclear matrix for proteasomal degradation.
Ontology highlight
ABSTRACT:
SUBMITTER: Yan P
PROVIDER: S-EPMC2676091 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Human T-cell leukemia virus type I (HTLV-I) encodes a Tax oncoprotein that has crucial roles in both virus replication and cell transformation. Our recent studies suggest that the counterbalance between HTLV-I/Tax and PDZ-LIM domain-containing protein PDLIM2 may determine the outcome of HTLV-I infection. Although HTLV-I represses PDLIM2 epigenetically and specifically in transformed cells, PDLIM2 shuttles Tax into the nuclear matrix for ubiquitination-mediated proteasomal degradation, thereby suppressing the transforming ability of HTLV-I. Here, we have further shown that PDLIM2 binds to Tax directly, which was mediated by a putative ?-helix motif of PDLIM2 at amino acids 236-254. Consistently, selective disruption of this short-helix crippled PDLIM2 in shutting Tax to the nuclear matrix for ubiquitination-mediated degradation, therefore, PDLIM2 lost the ability in tumor suppression. Although the C-terminal LIM domain of PDLIM2 was not required for Tax binding, it was important for PDLIM2 to interact with the nuclear matrix. Accordingly, the LIM domain was essential for PDLIM2-mediated Tax repression. On the contrary, the N-terminal PDZ domain of PDLIM2 was dispensable for all these events, although the PDZ domain was involved in PDLIM2 binding to cytoskeleton. These studies dissect functional sequences within PDLIM2 and their distinct roles in Tax regulation.
| S-EPMC3013277 | biostudies-other
Project description:Host encounters with viruses lead to an innate immune response that must be rapid and broadly targeted but also tightly regulated to avoid the detrimental effects of unregulated interferon expression. Viral stimulation of host negative regulatory mechanisms is an alternate method of suppressing the host innate immune response. We examined three key mediators of the innate immune response: NF-KB, STAT1 and STAT2 during HCV infection in order to investigate the paradoxical induction of an innate immune response by HCV despite a multitude of mechanisms combating the host response. During infection, we find that all three are repressed only in HCV infected cells but not in uninfected bystander cells, both in vivo in chimeric mouse livers and in cultured Huh7.5 cells after IFNα treatment. We show here that HCV and Flaviviruses suppress the innate immune response by upregulation of PDLIM2, independent of the host interferon response. We show PDLIM2 is an E3 ubiquitin ligase that also acts to stimulate nuclear degradation of STAT2. Interferon dependent relocalization of STAT1/2 to the nucleus leads to PDLIM2 ubiquitination of STAT2 but not STAT1 and the proteasome-dependent degradation of STAT2, predominantly within the nucleus. CRISPR/Cas9 knockout of PDLIM2 results in increased levels of STAT2 following IFNα treatment, retention of STAT2 within the nucleus of HCV infected cells after IFNα stimulation, increased interferon response, and increased resistance to infection by several flaviviruses, indicating that PDLIM2 is a global regulator of the interferon response.
| S-EPMC6677295 | biostudies-literature
Project description:BackgroundRecognition of viral invasion by innate antiviral immune system triggers activation of the type I interferon (IFN-I) and proinflammatory signaling pathways. Subsequently, IFN-I induction regulates expression of a group of genes known as IFN-I-stimulated genes (ISGs) to block viral infection. The tripartite motif containing 22 (TRIM22) is an ISG with strong antiviral functions.ResultsHere we have shown that the TRIM22 has been strongly upregulated both transcriptionally and translationally upon Zika virus (ZIKV) infection. ZIKV infection is associated with a wide range of clinical manifestations in human from mild to severe symptoms including abnormal fetal brain development. We found that the antiviral function of TRIM22 plays a crucial role in counterattacking ZIKV infection. Overexpression of TRIM22 protein inhibited ZIKV growth whereas deletion of TRIM22 in host cells increased ZIKV infectivity. Mechanistically, TRIM22, as a functional E3 ubiquitin ligase, promoted the ubiquitination and degradation of ZIKV nonstructural protein 1 (NS1) and nonstructural protein 3 (NS3). Further studies showed that the SPRY domain and Ring domain of TRIM22 played important roles in protein interaction and degradation, respectively. In addition, we found that TRIM22 also inhibited other flaviviruses infection including dengue virus (DENV) and yellow fever virus (YFV).ConclusionThus, TRIM22 is an ISG with important role in host defense against flaviviruses through binding and degradation of the NS1 and NS3 proteins.
| S-EPMC9429444 | biostudies-literature
Project description:Activation-induced cytidine deaminase (AID) initiates all postrearrangement processes that diversify the immunoglobulin repertoire by specific deamination of cytidines at the immunoglobulin (Ig) locus. As uncontrolled expression of AID is potentially mutagenic, different types of regulation, particularly nucleocytoplasmic shuttling, restrict the likelihood of AID-deoxyribonucleic acid encounters. We studied additional mechanisms of regulation affecting the stability of the AID protein. No modulation of protein accumulation according to the cell cycle was observed in a Burkitt's lymphoma cell line. In contrast, the half-life of AID was markedly reduced in the nucleus, and this destabilization was accompanied by a polyubiquitination that was revealed in the presence of proteasome inhibitors. The same compartment-specific degradation was observed in activated mouse B cells, and also in a non-B cell line. No specific lysine residues could be linked to this degradation, so it remains unclear whether polyubiquitination proceeds through several alternatives sites or through the protein N terminus. The nuclear-restricted form of AID displayed enhanced mutagenicity at both Ig and non-Ig loci, most notably at TP53, suggesting that modulation of nuclear AID content through proteasomal degradation may represent another level of control of AID activity.
| S-EPMC2413033 | biostudies-literature
Project description:The Wnt/?-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of ?-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic ?-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/?-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/?-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to ?-catenin, promoting its degradation, and specifically downregulates Wnt/?-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/?-catenin signaling pathway.
| S-EPMC4957947 | biostudies-literature
Project description:As a highly organized system, endo-lysosomes play a crucial role in maintaining immune homeostasis. However, the mechanisms involved in regulating endo-lysosome progression and subsequent inflammatory responses are not fully understood. By screening 103 E3 ubiquitin ligases in regulating endo-lysosomal acidification, it is discovered that lysosomal RNF13 inhibits lysosome maturation and promotes inflammatory responses mediated by endosomal Toll-like receptors (TLRs) in macrophages. Mechanistically, RNF13 mediates K48-linked polyubiquitination of LAMP-1 at residue K128 for proteasomal degradation. Upon TLRs activation, LAMP-1 promotes lysosomes maturation, which accelerates lysosomal degradation of TLRs and reduces TLR signaling in macrophages. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis (RA) show increased RNF13 levels and decreased LAMP-1 expression. Accordingly, the immunosuppressive agent hydroxychloroquine (HCQ) can increase the polyubiquitination of RNF13. Taken together, the study establishes a linkage between proteasomal and lysosomal degradation mechanisms for the induction of appropriate innate immune response, and offers a promising approach for the treatment of inflammatory diseases by targeting intracellular TLRs.
| S-EPMC11348240 | biostudies-literature
Project description:Increasing evidence supports that ELL (eleven-nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor.
| S-EPMC4820845 | biostudies-literature
Project description:MicroRNAs are small non‑coding RNA molecules which act as modulators of gene function, and have been identified as playing important roles in cancer as both tumor suppressors and oncogenes. The present study aimed to examine the role of miR‑198 in prostate cancer aggression by analyzing how it influences several hallmarks of cancer. Abundance of miR‑198 in prostate cancer and association with clinical characteristics was analyzed using a CPC‑Gene prostate cancer dataset. Overexpression of miR‑198 was performed using transient transfection of miR‑198 mimic prior to assaying proliferation, cell cycle, and colony formation in LNCaP and DU145 cell lines using standard protocols. In vivo tumor formation in athymic nude mice was examined using LNCaP xenografts with stable overexpression conferred using lentiviral miR‑198 transduction. Protein and mRNA abundance of MIB1 was determined using western blotting and RT‑qPCR respectively, while miR‑198 binding to MIB1 was validated using a luciferase reporter assay. miR‑198 abundance was lower in high Gleason grade prostate cancer relative to intermediate and low‑grade cancer. Overexpression of miR‑198 diminished proliferation of prostate cancer cell lines, increased G0/G1 cell cycle arrest, and significantly impaired colony formation. Elevated miR‑198 abundance was also demonstrated to impair tumor formation in vivo using LNCaP xenografts. Mindbomb E3 ubiquitin protein ligase 1 (MIB1) was demonstrated to be directly targeted by miR‑198, and knockdown of MIB1 recapitulated the effects of miR‑198 on proliferation and colony formation. The present evidence supports miR‑198 as an important tumor suppressor in prostate cancer, and demonstrates for the first time that it acts by targeting MIB1. The present study reinforces the importance and complexity of miRNA in regulating prostate cancer aggression.
| S-EPMC6667842 | biostudies-other
Project description:One of the most fundamental and challenging questions in the field of cancer is how immunity is transformed from tumor immunosurveillance to tumor-promoting inflammation. Here, we identified the tumor suppressor PDZ-LIM domain-containing protein 2 (PDLIM2) as a checkpoint of alveolar macrophages (AMs) important for lung tumor suppression. During lung tumorigenesis, PDLIM2 expression in AMs is downregulated by ROS-activated transcription repressor BTB and CNC homology 1 (BACH1). PDLIM2 downregulation leads to constitutive activation of the transcription factor STAT3, driving AM protumorigenic polarization/activation and differentiation from monocytes attracted from the circulation to suppress cytotoxic T lymphocytes and promote lung cancer. PDLIM2 downregulation also decreases AM phagocytosis. These findings establish ROS/BACH1/PDLIM2/STAT3 as a signaling pathway driving AMs for lung tumor promotion.
| S-EPMC8021114 | biostudies-literature
Project description:Inducing degradation of oncoproteins by small molecule compounds has the potential to avoid drug resistance and therefore deserves to be exploited for new therapies. Oridonin is a natural compound with promising antitumor efficacy that can trigger the degradation of oncoproteins; however, the direct cellular targets and underlying mechanisms remain unclear. Here we report that oridonin depletes BCR-ABL through chaperon-mediated proteasomal degradation in leukemia. Mechanistically, oridonin poses oxidative stress in cancer cells and directly binds to cysteines of HSF1, leading to the activation of this master regulator of the chaperone system. The resulting induction of HSP70 and ubiquitin proteins and the enhanced binding to CHIP E3 ligase hence target BCR-ABL for ubiquitin-proteasome degradation. Both wild-type and mutant forms of BCR-ABL can be efficiently degraded by oridonin, supporting its efficacy observed in cultured cells as well as mouse tumor xenograft assays with either imatinib-sensitive or -resistant cells. Collectively, our results identify a novel mechanism by which oridonin induces rapid degradation of BCR-ABL as well as a novel pharmaceutical activator of HSF1 that represents a promising treatment for leukemia.
| S-EPMC5270248 | biostudies-literature