Human herpesvirus-8-encoded LNA-1 accumulates in heterochromatin- associated nuclear bodies

Szekeres, L.; Kiss, Csaba; Mattsson, Karin; Kashuba, Elena; Pokrovskaja, Katja; Juhász, Attila; Holmvall, Pia; Klein, George

doi:10.1099/0022-1317-80-11-2889

Cited by 88 publications

(97 citation statements)

References 33 publications

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“…Both N-terminal LANA (N-LANA) and C-terminal LANA (C-LANA) are essential for function. N-LANA associates with mitotic chromosomes via binding histones H2A/H2B, and C-LANA simultaneously binds KSHV terminal repeat (TR) DNA (7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Thus, LANA tethers the viral genome to host chromosomes and distributes viral DNA to daughter nuclei during mitosis.…”

Section: Oss-mentioning

confidence: 99%

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Sun

Tsurimoto

Juillard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Kaposi's sarcoma herpesvirus (KSHV) latently infects tumor cells, and viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV latency-associated nuclear antigen (LANA) recruits host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show LANA recruits replication factor C, the DNA polymerase clamp [proliferating cell nuclear antigen (PCNA)] loader, in a critical step for viral DNA replication. Our findings suggest that PCNA loading is a rate-limiting step in DNA replication that is incompatible with KSHV persistence. LANA-enhanced PCNA loading is necessary for virus replication and persistent infection. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells.

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Section: Oss-mentioning

confidence: 99%

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Sun

Tsurimoto

Juillard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…17 The LANA protein is encoded by the open-reading frame 73 (ORF73) of the HHV-8 genome, where it tethers viral DNA to host heterochromatin and is thereby required for persistence of viral DNA in dividing cells. 18,19 LANA is also capable of interacting with pRb, which plays a regulatory role in the beginning of the S-phase of the cell cycle. 20 Additionally, LANA mimics the E6 and E7 viral oncoproteins of human papillomavirus in its ability to inhibit the function of p53.…”

Section: Discussionmentioning

confidence: 99%

Latency-associated nuclear antigen expression and human herpesvirus-8 polymerase chain reaction in the evaluation of Kaposi sarcoma and other vascular tumors in HIV-positive patients

et al. 2005

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Human herpesvirus-8 (HHV-8) latency-associated nuclear antigen (LANA) is expressed in endothelial and spindle cells of nearly all Kaposi sarcomas, and the presence of this antigen in serum is strongly correlated with the risk of developing Kaposi sarcoma in immunocompromised individuals. Studies of vascular tumors occurring in the general population show LANA expression to be specific for Kaposi sarcoma. No study to date, however, has examined whether non-Kaposi sarcoma vascular tumors arising in immunocompromised patients may express LANA, possibly reflecting origin from an HHV-8-infected endothelial progenitor cell. The objective of this study was to evaluate the specificity of LANA expression for Kaposi sarcoma in immunocompromised patients by LANA immunohistochemistry and real-time polymerase chain reaction (PCR) for HHV-8. A total of 13 cases of non-Kaposi sarcoma vascular tumors (12 hemangiomas and one epithelioid hemangioendothelioma) and 24 cases of Kaposi sarcoma, all from known HIV-positive patients, were immunostained for LANA and evaluated for the presence of HHV-8 DNA by real-time PCR. LANA expression was seen in 22 of 24 (92%) of Kaposi sarcoma cases and in 0 of 13 non-Kaposi sarcoma cases. Real-time PCR detected HHV-8 in all of the Kaposi sarcoma cases and in four of the non-Kaposi sarcoma cases (all hemangiomas). LANA expression appears to be a highly sensitive and specific marker of Kaposi sarcoma in both the general population and in HIV-positive patients. This is in contrast to HHV-8 PCR, which is positive in a small subset of non-Kaposi sarcoma vascular tumors, most likely due to detection of HHV-8 within intratumoral blood mononuclear cells by the highly sensitive real-time PCR technique. For this reason, LANA immunohistochemistry is preferable to HHV-8 PCR for the evaluation of problematic vascular proliferations in HIV-positive individuals.

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“…The images were captured with a PXL cooled CCD camera (Photometrix). Image processing was provided by the imaging program ST-FITC-Rhodamine-Hoecshtbin1 (18), which produces both single and stereo-projected three-color images from a series of wide field pictures where the out-of-focus blur was removed by nearest neighbor deconvolution and the images were built up using a maximum intensity projection algorithm.…”

Section: Methodsmentioning

confidence: 99%

Identification of ERp29, an Endoplasmic Reticulum Lumenal Protein, as a New Member of the Thyroglobulin Folding Complex

Sargsyan¹,

Барышев²,

Szekeres³

et al. 2002

Journal of Biological Chemistry

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Folding and post-translational modification of the thyroid hormone precursor, thyroglobulin (Tg), in the endoplasmic reticulum (ER) of the thyroid epithelial cells is facilitated by several molecular chaperones and folding enzymes, such as BiP, GRP94, calnexin, protein disulfide isomerase, ERp72, and others. They have been shown to associate simultaneously and/or sequentially with Tg in the course of its maturation, thus forming large heterocomplexes in the ER of thyrocytes. Here we present evidence that such complexes include a novel member, an ER-resident lumenal protein, ERp29, which is present in all mammalian tissues with exceptionally high levels of expression in the secretory cells. ERp29 was induced upon treatment of FRTL-5 rat thyrocytes with the thyroid-stimulating hormone, which is essential for the maintenance of thyroid cells and Tg biosynthesis. Chemical cross-linking followed by the cell lysis and immunoprecipitation of ERp29 or Tg revealed association of these proteins and additionally, immunocomplexes that also included major ER chaperones, BiP and GRP94. Sucrose density gradient analysis indicated colocalization of ERp29 with Tg and BiP in the fractions containing large macromolecular complexes. This was supported by immunofluorescent microscopy showing co-localization of ERp29 with Tg in the putative transport vesicular structures. Affinity chromatography using Tg as an affinity ligand demonstrated that ERp29 might be selectively isolated from the FRTL-5 cell lysate or purified lumenal fraction of rat liver microsomes along with the other ER chaperones. Preferential association with the urea-denatured Tg-Sepharose was indicative of either direct or circuitous ERp29/Tg interactions in a chaperone-like manner. Despite the presence of the C-terminal ER-retrieval signal, significant amounts of ERp29 were also recovered from the culture medium of stimulated thyrocytes, indicating ERp29 secretion. Based on these data, we suggest that the function of ERp29 in thyroid cells is connected with folding and/or secretion of Tg.

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Human herpesvirus-8-encoded LNA-1 accumulates in heterochromatin- associated nuclear bodies

Cited by 88 publications

References 33 publications

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Latency-associated nuclear antigen expression and human herpesvirus-8 polymerase chain reaction in the evaluation of Kaposi sarcoma and other vascular tumors in HIV-positive patients

Identification of ERp29, an Endoplasmic Reticulum Lumenal Protein, as a New Member of the Thyroglobulin Folding Complex

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