Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.
ABSTRACT USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.
SourceAvailable from: Mohamed-Ali Hakimi[Show abstract] [Hide abstract]
ABSTRACT: The obligate intracellular parasite Toxoplasma gondii strikes a subtle balance with the host immune system that not only prevents host death but also promotes parasite persistence. Although being enclosed within a parasitophorous vacuole, the parasite actively interfaces with host cell signaling pathways, thereby directing host cell responses. To this end, T. gondii delivers effector proteins into the host cell that co-opt host transcription factors and eventually modulate gene expression. Aside from the secretory Rhoptry organelles initially described as the main source of such effectors, Dense Granules are now recognized as critical in delivering products that remain confined at the vacuolar space or traffic beyond the vacuole membrane to the host cell nucleus and contribute to rewire host gene expression. This review highlights the latest breakthroughs in T. gondii effector discovery and their modus operandi during infection.
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ABSTRACT: Deubiquitinases (DUBs) play important roles and therefore are potential drug targets in various diseases including cancer and neurodegeneration. In this review, we recapitulate structure-function studies of the most studied DUBs including USP7, USP22, CYLD, UCHL1, BAP1, A20, as well as ataxin 3 and connect them to regulatory mechanisms and their growing protein interaction networks. We then describe DUBs that have been associated with endocrine carcinogenesis with a focus on prostate, ovarian, and thyroid cancer, pheochromocytoma, and adrenocortical carcinoma. The goal is enhancing our understanding of the connection between dysregulated DUBs and cancer to permit the design of therapeutics and to establish biomarkers that could be used in diagnosis and prognosis. © 2015 The authors.Endocrine Related Cancer 02/2015; 22(1):T35-T54. DOI:10.1530/ERC-14-0516 · 4.91 Impact Factor
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ABSTRACT: Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype that accounts for nearly 10% of gastric carcinomas. EBVaGC is defined by monoclonal proliferation of carcinoma cells with latent EBV infection, as demonstrated by EBV-encoded small RNA (EBER) in situ hybridization. EBVaGC has characteristic clinicopathological features, including predominance among males, a proximal location in the stomach, lymphoepithelioma-like histology and a favorable prognosis. EBVaGC belongs to latency type I or II, in which EBERs, EBNA-1, BARTs, LMP-2A and BART miRNAs are expressed. Previous studies have shown that some EBV latent genes have oncogenic properties. Recent advances in genome-wide and comprehensive molecular analyses have demonstrated that both genetic and epigenetic changes contribute to EBVaGC carcinogenesis. Genetic changes that are characteristic of EBVaGC include frequent mutations in PIK3CA and ARID1A and amplification of JAK2 and PD-L1/L2. Global CpG island hypermethylation, which induces epigenetic silencing of tumor suppressor genes, is also a unique feature of EBVaGC and is considered to be crucial for its carcinogenesis. Furthermore, post-transcriptional gene expression regulation by cellular and/or EBV-derived microRNAs has attracted considerable attention. These abnormalities result in significant alterations in gene expression related to cell proliferation, apoptosis, migration and immune signaling pathways. In the present review we highlight the latest findings on EBVaGC from clinicopathological and molecular perspectives to provide a better understanding of EBV involvement in gastric carcinogenesis.International Journal of Oncology 01/2015; 46(4). DOI:10.3892/ijo.2015.2856 · 2.77 Impact Factor