المؤلفون: Yulin Zhang¹, Zhongwei Dong¹, Feng Gu¹, Yifei Xu¹, Ying Li¹, Wen Sun¹, Wutian Rao¹, Shujuan Du¹, Caixia Zhu¹, Yuyan Wang¹ yuyanss@fudan.edu.cn, Fang Wei² fangwei@sjtu.edu.cn, Qiliang Cai¹ qiliang@fudan.edu.cn

المصدر: Journal of Virology. Jun2024, Vol. 98 Issue 6, p1-20. 20p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *KAPOSI'S sarcoma, *VIRUS diseases, *VIRUS reactivation

مستخلص: TRIM32 is often aberrantly expressed in many types of cancers. Kaposi’s sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi’s sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi’s sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers. [ABSTRACT FROM AUTHOR]

المؤلفون: Han, Chunyan¹ (AUTHOR), Gui, Chenwu¹ (AUTHOR), Dong, Shuhong¹ (AUTHOR), Lan, Ke^1,2,3 (AUTHOR) klan@whu.edu.cn

المصدر: Viruses (1999-4915). May2024, Vol. 16 Issue 5, p749. 17p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *ONCOGENIC DNA viruses, *LATENT infection, *KAPOSI'S sarcoma, *CELL communication, *CD30 antigen, *VENOM

مستخلص: During viral infection, the innate immune system utilizes a variety of specific intracellular sensors to detect virus-derived nucleic acids and activate a series of cellular signaling cascades that produce type I IFNs and proinflammatory cytokines and chemokines. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus that has been associated with a variety of human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Infection with KSHV activates various DNA sensors, including cGAS, STING, IFI16, and DExD/H-box helicases. Activation of these DNA sensors induces the innate immune response to antagonize the virus. To counteract this, KSHV has developed countless strategies to evade or inhibit DNA sensing and facilitate its own infection. This review summarizes the major DNA-triggered sensing signaling pathways and details the current knowledge of DNA-sensing mechanisms involved in KSHV infection, as well as how KSHV evades antiviral signaling pathways to successfully establish latent infection and undergo lytic reactivation. [ABSTRACT FROM AUTHOR]

المؤلفون: Lopez, Melanie¹ (AUTHOR), Kainthla, Radhika^2,3 (AUTHOR), Lazarte, Susana^3,4 (AUTHOR), Chen, Weina⁵ (AUTHOR), Nijhawan, Ank E.^3,4 (AUTHOR), Knights, Sheena^3,4 (AUTHOR) sheena.knights@utsouthwestern.edu

المصدر: European Journal of Haematology. May2024, Vol. 112 Issue 5, p723-730. 8p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *CASTLEMAN'S disease, *HIV, *HOSPITALS, *EXUDATES & transudates

مصطلحات جغرافية: DALLAS (Tex.)

مستخلص: Objective: To describe cases of Kaposi's sarcoma‐associated herpesvirus (KSHV)‐associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety‐net hospital system in Dallas, Texas, USA. Methods: We conducted a retrospective review of patients with HIV‐associated PEL and/or MCD. Results: Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow‐up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3–6‐month median survival historically. Median follow‐up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. Conclusion: These data highlight the importance of early recognition of PEL and MCD, and the larger‐scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV‐related diseases. [ABSTRACT FROM AUTHOR]

المؤلفون: Zhou, Yaru^1,2,3 (AUTHOR), Tian, Xuezhang^1,2 (AUTHOR), Wang, Shaowei^1,2 (AUTHOR), Gao, Ming^1,2 (AUTHOR), Zhang, Chuchu^1,2 (AUTHOR), Ma, Jiali^1,2 (AUTHOR), Cheng, Xi^1,2 (AUTHOR), Bai, Lei⁴ (AUTHOR), Qin, Hai-Bin^5,6 (AUTHOR), Luo, Min-Hua^5,6 (AUTHOR), Qin, Qingsong⁷ (AUTHOR), Jiang, Baishan² (AUTHOR), Lan, Ke^2,4 (AUTHOR), Zhang, Junjie^1,2,3 (AUTHOR) junjiezhang@whu.edu.cn

المصدر: PLoS Pathogens. 4/16/2024, Vol. 20 Issue 4, p1-23. 23p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *PALMITOYLATION, *VIRION, *LIFE cycles (Biology), *VIRAL proteins

مستخلص: Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remains elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies. Author summary: Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple human malignancies. Nonetheless, the roles of numerous viral proteins in the viral life cycle remain inadequately characterized. Employing CRISPR knockout screening, we identified the viral tegument protein pORF55 as pivotal in the production of infectious progeny virions. We found that pORF55 is palmitoylated at cysteine 10 and 11, which is required for its Golgi localization. Palmitoylation-deficient mutants of pORF55 are unstable and fail to support secondary envelopment formation, a critical step for viral assembly and egress. Interestingly, we found that forced restoration of the Golgi localization of the palmitoylation-deficient pORF55 mutants completely reinstates the infectious progeny virion production. Hence, our study underscores the central role of Golgi localization resulting from pORF55 palmitoylation. Our study not only elucidates the role of pORF55 in viral replication, but also suggests targeting its palmitoylation as a potential therapeutic strategy for curtailing viral replication and treating related pathogenesis. [ABSTRACT FROM AUTHOR]

المؤلفون: Zhou, Jing¹ (AUTHOR), Wang, Tianjiao¹ (AUTHOR), Zhang, Haoran¹ (AUTHOR), Liu, Jianhong² (AUTHOR), Wei, Pengjun¹ (AUTHOR), Xu, Ruoqi¹ (AUTHOR), Yan, Qin^1,3,4 (AUTHOR) yanqin@njmu.edu.cn, Chen, Guochun⁵ (AUTHOR) yanqin@njmu.edu.cn, Li, Wan^1,3,4 (AUTHOR) yanqin@njmu.edu.cn, Gao, Shou-Jiang⁶ (AUTHOR), Lu, Chun^1,3,4 (AUTHOR) yanqin@njmu.edu.cn

المصدر: PLoS Pathogens. 3/12/2024, Vol. 20 Issue 3, p1-25. 25p.

مصطلحات موضوعية: *CELL transformation, *KAPOSI'S sarcoma-associated herpesvirus, *DEACETYLATION, *ACETYLATION, *CARRIER proteins

مستخلص: Ferroptosis, a defensive strategy commonly employed by the host cells to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of cancer. However, the role of ferroptosis in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers remains elusive. While a growing number of non-histone proteins have been identified as acetylation targets, the functions of these modifications have yet to be revealed. Here, we show KSHV reprogramming of host acetylation proteomics following cellular transformation of rat primary mesenchymal precursor. Among them, SERPINE1 mRNA binding protein 1 (SERBP1) deacetylation is increased and required for KSHV-induced cellular transformation. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. Consequently, a SIRT3-specific inhibitor, 3-TYP, suppresses KSHV-induced cellular transformation by inducing ferroptosis. Our findings unveil novel roles of vIL-6 and SERBP1 deacetylation in regulating ferroptosis and KSHV-induced cellular transformation, and establish the vIL-6-SIRT3-SERBP1-ferroptosis pathways as a potential new therapeutic target for KSHV-associated cancers. Author summary: Ferroptosis has been implicated in viral infections and the development of cancers, however, its role in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers is still unknown. Although abnormal protein lysine acetylation modification has been strongly implicated in tumorigenesis, the exact role of this modification in KSHV-induced cell transformation remains elusive. Our study uncovers the reduction of acetylation of SERPINE1 mRNA binding protein 1 (SERBP1), which is required for KSHV-induced cellular transformation. KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. A SIRT3-specific inhibitor, 3-TYP, induces ferroptosis and inhibits survival of KSHV-transformed cells. These findings define a novel mechanism contributing to KSHV-induced cellular transformation and provide a rationale for therapeutically targeting lysine acetylation and the associated enzyme for infectious diseases. [ABSTRACT FROM AUTHOR]

المؤلفون: Li, Fangling^1,2 (AUTHOR) lifanglingcdd@sina.com, Cao, Dongdong¹ (AUTHOR) caodongd@shzu.edu.cn, Gu, Wenyi³ (AUTHOR) w.gu@uq.edu.au, Li, Dongmei¹ (AUTHOR) cuilin@shzu.edu.cn, Liu, Zhiyong² (AUTHOR) lidongmei@shzu.edu.cn, Cui, Lin¹ (AUTHOR)

المصدر: International Journal of Molecular Sciences. Mar2024, Vol. 25 Issue 5, p2932. 19p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *GANCICLOVIR, *NANOCARRIERS, *FOLIC acid, *GENE expression, *NUCLEIC acids

مستخلص: Kaposi's sarcoma-associated herpesvirus (KSHV) can cause a variety of malignancies. Ganciclovir (GCV) is one of the most efficient drugs against KSHV, but its non-specificity can cause other side effects in patients. Nucleic acid miR-34a-5p can inhibit the transcription of KSHV RNA and has great potential in anti-KSHV therapy, but there are still problems such as easy degradation and low delivery efficiency. Here, we constructed a co-loaded dual-drug nanocomplex (GCV@ZIF-8/PEI-FA+miR-34a-5p) that contains GCV internally and adsorbs miR-34a-5p externally. The folic acid (FA)-coupled polyethyleneimine (PEI) coating layer (PEI-FA) was shown to increase the cellular uptake of the nanocomplex, which is conducive to the enrichment of drugs at the KSHV infection site. GCV and miR-34a-5p are released at the site of the KSHV infection through the acid hydrolysis characteristics of ZIF-8 and the "proton sponge effect" of PEI. The co-loaded dual-drug nanocomplex not only inhibits the proliferation and migration of KSHV-positive cells but also decreases the mRNA expression level of KSHV lytic and latent genes. In conclusion, this co-loaded dual-drug nanocomplex may provide an attractive strategy for antiviral drug delivery and anti-KSHV therapy. [ABSTRACT FROM AUTHOR]

المؤلفون: Pengyu Ren¹, Danping Niu¹, Sijia Chang¹, Lei Yu¹, Junrui Ren¹, Yuanming Ma¹, Ke Lan^1,2,3 klan@whu.edu.cn

المصدر: Journal of Virology. Feb2024, Vol. 98 Issue 2, p1-21. 21p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *VIRAL replication, *VIRAL genomes, *LATENT infection, *LIFE cycles (Biology), *VIRAL genes

مستخلص: Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma herpesvirus family, which can cause human malignancies including Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman’s diseases. KSHV typically maintains a persistent latent infection within the host. However, after exposure to intracellular or extracellular stimuli, KSHV lytic replication can be reactivated. The reactivation process of KSHV triggers the innate immune response to limit viral replication. Here, we found that the transcriptional regulator RUNX3 is transcriptionally upregulated by the NF-κB signaling pathway in KSHV-infected SLK cells and B cells during KSHV reactivation. Notably, knockdown of RUNX3 significantly promotes viral lytic replication as well as the gene transcription of KSHV. Consistent with this finding, overexpression of RUNX3 impairs viral lytic replication. Mechanistically, RUNX3 binds to the KSHV genome and limits viral replication through transcriptional repression, which is related to its DNA- and ATP-binding ability. However, KSHV has also evolved corresponding strategies to antagonize this inhibition by using the viral protein RTA to target RUNX3 for ubiquitination and proteasomal degradation. Altogether, our study suggests that RUNX3, a novel host-restriction factor of KSHV that represses the transcription of viral genes, may serve as a potential target to restrict KSHV transmission and disease development. IMPORTANCE The reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV) from latent infection to lytic replication is important for persistent viral infection and tumorigenicity. However, reactivation is a complex event, and the regulatory mechanisms of this process are not fully elucidated. Our study revealed that the host RUNX3 is upregulated by the NF-κB signaling pathway during KSHV reactivation, which can repress the transcription of KSHV genes. At the late stage of lytic replication, KSHV utilizes a mechanism involving RTA to degrade RUNX3, thus evading host inhibition. This finding helps elucidate the regulatory mechanism of the KSHV life cycle and may provide new clues for the development of therapeutic strategies for KSHV-associated diseases. [ABSTRACT FROM AUTHOR]

المؤلفون: Ken-ichi Nakajima¹ kennakajima@ucdavis.edu, Tomoki Inagaki¹, Espera, Jonna Magdallene¹, Yoshihiro Izumiya¹ yizumiya@ucdavis.edu

المصدر: Journal of Virology. Feb2024, Vol. 98 Issue 2, p1-18. 18p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *BACTERIAL artificial chromosomes, *GENE expression, *EPISOMES, *INTERFERONS, *VIRAL DNA, *TYPE I interferons

مستخلص: Protein knockdown with an inducible degradation system is a powerful tool for studying proteins of interest in living cells. Here, we adopted the auxininducible degron (AID) approach to detail Kaposi’s sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) function in latency maintenance and inducible viral lytic gene expression. We fused the mini-auxin-inducible degron (mAID) tag at the LANA N-terminus with KSHV bacterial artificial chromosome 16 recombination, and iSLK cells were stably infected with the recombinant KSHV encoding mAID-LANA. Incubation with 5-phenyl-indole-3-acetic acid, a derivative of natural auxin, rapidly degraded LANA within 1.5 h. In contrast to our hypothesis, depletion of LANA alone did not trigger lytic reactivation but rather decreased inducible lytic gene expression when we stimulated reactivation with a combination of ORF50 protein expression and sodium butyrate. Decreased overall lytic gene induction seemed to be associated with a rapid loss of KSHV genomes in the absence of LANA. The rapid loss of viral genomic DNA was blocked by a lysosomal inhibitor, chloroquine. Furthermore, siRNA-mediated knockdown of cellular innate immune proteins, cyclic AMP-GMP synthase (cGAS) and simulator of interferon genes (STING), and other autophagy-related genes rescued the degradation of viral genomic DNA upon LANA depletion. Reduction of the viral genome was not observed in 293FT cells that lack the expression of cGAS. These results suggest that LANA actively prevents viral genomic DNA from sensing by cGAS-STING signaling axis, adding novel insights into the role of LANA in latent genome maintenance. IMPORTANCE Sensing of pathogens’ components is a fundamental cellular immune response. Pathogens have therefore evolved strategies to evade such cellular immune responses. KSHV LANA is a multifunctional protein and plays an essential role in maintaining the latent infection by tethering viral genomic DNA to the host chromosome. We adopted the inducible protein knockdown approach and found that depletion of LANA induced rapid degradation of viral genomic DNA, which is mediated by innate immune DNA sensors and autophagy pathway. These observations suggest that LANA may play a role in hiding KSHV episome from innate immune DNA sensors. Our study thus provides new insights into the role of LANA in latency maintenance. [ABSTRACT FROM AUTHOR]

المؤلفون: Yoshihiro Izumiya^1,2 yizumiya@ucdavis.edu, Algalil, Adhraa^1,3, Espera, Jonna M.¹, Hiroki Miura¹, Chie Izumiya¹, Tomoki Inagaki¹, Kumar, Ashish¹

المصدر: Journal of Virology. Feb2024, Vol. 98 Issue 2, p1-22. 22p.

مصطلحات موضوعية: *KAPOSI'S sarcoma-associated herpesvirus, *THYROID hormone receptors, *GENE enhancers, *GENE expression, *BINDING sites, *REGULATOR genes, *VIRAL genes

مستخلص: The Kaposi’s sarcoma-associated herpesvirus (KSHV) genome consists of an approximately 140-kb unique coding region flanked by 30-40 copies of a 0.8-kb terminal repeat (TR) sequence. A gene enhancer recruits transcription-related enzymes by having arrays of transcription factor binding sites. Here, we show that KSHV TR possesses transcription regulatory function with latency-associated nuclear antigen (LANA). Cleavage under targets and release using nuclease demonstrated that TR fragments were occupied by LANA-interacting histone-modifying enzymes in naturally infected cells. The TR was enriched with histone H3K27 acetylation (H3K27Ac) and H3K4 tri-methylation (H3K4me3) modifications and also expressed nascent RNAs. The sites of H3K27Ac and H3K4me3 modifications were also conserved in the KSHV unique region among naturally infected primary effusion lymphoma cells. KSHV origin of lytic replication (Ori-Lyt) showed similar protein and histone modification occupancies with that of TR. In the Ori-Lyt region, the LANA and LANA-interacting proteins colocalized with an H3K27Ac-modified nucleosome along with paused RNA polymerase II. The KSHV transactivator KSHV replication and transcription activator (K-Rta) recruitment sites franked the LANA-bound nucleosome, and reactivation evicted the LANA-bound nucleosome. Including TR fragments in reporter plasmid enhanced inducible viral gene promoter activities independent of the orientations. In the presence of TR in reporter plasmids, K-Rta transactivation was drastically increased, while LANA acquired the promoter repression function. KSHV TR, therefore, functions as an enhancer for KSHV inducible genes. However, in contrast to cellular enhancers bound by multiple transcription factors, perhaps the KSHV enhancer is predominantly regulated by the LANA nuclear body. IMPORTANCE Enhancers are a crucial regulator of differential gene expression programs. Enhancers are the cis-regulatory sequences determining target genes’ spatiotemporal and quantitative expression. Here, we show that Kaposi’s sarcoma-associated herpesvirus (KSHV) terminal repeats fulfill the enhancer definition for KSHV inducible gene promoters. The KSHV enhancer is occupied by latency-associated nuclear antigen (LANA) and its interacting proteins, such as CHD4. Neighboring terminal repeat (TR) fragments to lytic gene promoters drastically enhanced KSHV replication and transcription activator and LANA transcription regulatory functions. This study, thus, proposes a new latency-lytic switch model in which TR accessibility to the KSHV gene promoters regulates viral inducible gene expression. [ABSTRACT FROM AUTHOR]

المؤلفون: Izumiya, Yoshihiro, Algalil, Adhraa, Espera, Jonna M, Miura, Hiroki, Izumiya, Chie, Inagaki, Tomoki, Kumar, Ashish

المصدر: Journal of Virology. 98(2)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biological Sciences, Emerging Infectious Diseases, Infectious Diseases, Lymphoma, Cancer, Hematology, Lymphatic Research, Rare Diseases, Genetics, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Infection, Generic health relevance, Humans, Herpesvirus 8, Human, Histones, Nucleosomes, Immediate-Early Proteins, Virus Latency, Antigens, Viral, Terminal Repeat Sequences, Gene Expression Regulation, Viral, Sarcoma, Kaposi, Kaposi's sarcoma-associated herpesvirus, transcriptional regulation, reactivation, RNA polymerases, latency, enhancer, BRD4, CHD4, herpesviruses, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology, Agricultural, veterinary and food sciences, Biological sciences, Biomedical and clinical sciences

الوصف: The Kaposi's sarcoma-associated herpesvirus (KSHV) genome consists of an approximately 140-kb unique coding region flanked by 30-40 copies of a 0.8-kb terminal repeat (TR) sequence. A gene enhancer recruits transcription-related enzymes by having arrays of transcription factor binding sites. Here, we show that KSHV TR possesses transcription regulatory function with latency-associated nuclear antigen (LANA). Cleavage under targets and release using nuclease demonstrated that TR fragments were occupied by LANA-interacting histone-modifying enzymes in naturally infected cells. The TR was enriched with histone H3K27 acetylation (H3K27Ac) and H3K4 tri-methylation (H3K4me3) modifications and also expressed nascent RNAs. The sites of H3K27Ac and H3K4me3 modifications were also conserved in the KSHV unique region among naturally infected primary effusion lymphoma cells. KSHV origin of lytic replication (Ori-Lyt) showed similar protein and histone modification occupancies with that of TR. In the Ori-Lyt region, the LANA and LANA-interacting proteins colocalized with an H3K27Ac-modified nucleosome along with paused RNA polymerase II. The KSHV transactivator KSHV replication and transcription activator (K-Rta) recruitment sites franked the LANA-bound nucleosome, and reactivation evicted the LANA-bound nucleosome. Including TR fragments in reporter plasmid enhanced inducible viral gene promoter activities independent of the orientations. In the presence of TR in reporter plasmids, K-Rta transactivation was drastically increased, while LANA acquired the promoter repression function. KSHV TR, therefore, functions as an enhancer for KSHV inducible genes. However, in contrast to cellular enhancers bound by multiple transcription factors, perhaps the KSHV enhancer is predominantly regulated by the LANA nuclear body.IMPORTANCEEnhancers are a crucial regulator of differential gene expression programs. Enhancers are the cis-regulatory sequences determining target genes' spatiotemporal and quantitative expression. Here, we show that Kaposi's sarcoma-associated herpesvirus (KSHV) terminal repeats fulfill the enhancer definition for KSHV inducible gene promoters. The KSHV enhancer is occupied by latency-associated nuclear antigen (LANA) and its interacting proteins, such as CHD4. Neighboring terminal repeat (TR) fragments to lytic gene promoters drastically enhanced KSHV replication and transcription activator and LANA transcription regulatory functions. This study, thus, proposes a new latency-lytic switch model in which TR accessibility to the KSHV gene promoters regulates viral inducible gene expression.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/44g4g5d4Test
https://escholarship.org/content/qt44g4g5d4/qt44g4g5d4.pdfTest