RESUMEN
Discovered in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with four human malignancies including Kaposi's sarcoma, primary effusion lymphoma, a subset of multicentric Castleman's disease, and KSHV inflammatory cytokine syndrome. These malignancies mostly occur in immunocompromised patients including patients with acquired immunodeficiency syndrome and often cause significant mortality because of the lack of effective therapies. Significant progresses have been made to understand the molecular basis of KSHV infection and KSHV-induced oncogenesis in the last two decades. This chapter provides an update on the recent advancements focusing on the molecular events of KSHV primary infection, the mechanisms regulating KSHV life cycle, innate and adaptive immunity, mechanism of KSHV-induced tumorigenesis and inflammation, and metabolic reprogramming in KSHV infection and KSHV-transformed cells.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/virología , Infecciones por Herpesviridae/genética , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/inmunología , Neoplasias/virología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Carcinogénesis/genética , Carcinogénesis/inmunología , Enfermedad de Castleman/fisiopatología , Enfermedad de Castleman/virología , Coinfección/virología , Citocinas/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Herpesvirus Humano 8/fisiología , Humanos , Huésped Inmunocomprometido , Inflamación/inmunología , Inflamación/fisiopatología , Inflamación/virología , Linfoma de Efusión Primaria/fisiopatología , Linfoma de Efusión Primaria/virología , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/fisiopatología , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/virología , Síndrome , Viremia/inmunología , Viremia/fisiopatología , Viremia/virologíaRESUMEN
mTORC1, a central controller of cell proliferation in response to growth factors and nutrients, is dysregulated in cancer. Whereas arginine activates mTORC1, it is overridden by high expression of cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Because cancer cells often encounter low levels of nutrients, an alternative mechanism might exist to regulate CASTOR1 expression. Here we show K29-linked polyubiquitination and degradation of CASTOR1 by E3 ubiquitin ligase RNF167. Furthermore, AKT phosphorylates CASTOR1 at S14, significantly increasing its binding to RNF167, and hence its ubiquitination and degradation, while simultaneously decreasing its affinity to MIOS, leading to mTORC1 activation. Therefore, AKT activates mTORC1 through both TSC2- and CASTOR1-dependent pathways. Several cell types with high CASTOR1 expression are insensitive to arginine regulation. Significantly, AKT and RNF167-mediated CASTOR1 degradation activates mTORC1 independent of arginine and promotes breast cancer progression. These results illustrate a mTORC1 regulating mechanism and identify RNF167 as a therapeutic target for mTORC1-dysregulated diseases.
Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteolisis , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Animales , Arginina/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Femenino , Péptidos y Proteínas de Señalización Intercelular/farmacología , Cinética , Lisina/metabolismo , Ratones Desnudos , Fosforilación/efectos de los fármacos , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
Viruses are associated with up to 15% of human cancer. MicroRNAs (miRNAs) encoded by numerous oncogenic viruses including Kaposi's sarcoma-associated herpesvirus (KSHV) play significant roles in regulating the proliferation and survival of virus-induced cancer cells, hence representing attractive therapeutic targets. Here, we report that specific inhibition of viral miRNAs by carbon dots (Cdots)-mediated delivery of locked nucleic acid (LNA)-based suppressors inhibit the proliferation of KSHV-associated primary effusion lymphoma (PEL) cells. Specifically, a combination of Cdots-LNAs to knock down the levels of KSHV miR-K12-1, miR-K12-4, and miR-K12-11 induces apoptosis and inhibits proliferation of PEL cells. Significantly, these Cdots-LNAs effectively inhibit the initiation of PEL and regress established PEL in a xenograft mouse model. These results demonstrate the feasibility of using Cdots to deliver miRNA suppressors for targeting viral cancers. Our study with viral miRNAs as targets may provide the scientific basis for using antisense drugs for human cancers associated with oncogenic viruses.
Asunto(s)
Antineoplásicos/farmacología , Carbono/química , Herpesvirus Humano 8/química , Linfoma/tratamiento farmacológico , Oligonucleótidos/farmacología , ARN Viral/antagonistas & inhibidores , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Linfoma/patología , Linfoma/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/virología , Oligonucleótidos/química , Tamaño de la Partícula , Puntos Cuánticos/química , Ratas , Propiedades de SuperficieRESUMEN
N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) modifications (m6A/m) of messenger RNA mediate diverse cellular functions. Oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) has latent and lytic replication phases that are essential for the development of KSHV-associated cancers. To date, the role of m6A/m in KSHV replication and tumorigenesis is unclear. Here, we provide mechanistic insights by examining the viral and cellular m6A/m epitranscriptomes during KSHV latent and lytic infection. KSHV transcripts contain abundant m6A/m modifications during latent and lytic replication, and these modifications are highly conserved among different cell types and infection systems. Knockdown of YTHDF2 enhanced lytic replication by impeding KSHV RNA degradation. YTHDF2 binds to viral transcripts and differentially mediates their stability. KSHV latent infection induces 5' untranslated region (UTR) hypomethylation and 3'UTR hypermethylation of the cellular epitranscriptome, regulating oncogenic and epithelial-mesenchymal transition pathways. KSHV lytic replication induces dynamic reprogramming of epitranscriptome, regulating pathways that control lytic replication. These results reveal a critical role of m6A/m modifications in KSHV lifecycle and provide rich resources for future investigations.
Asunto(s)
Adenosina/análogos & derivados , Infecciones por Herpesviridae/genética , Herpesvirus Humano 8/genética , ARN Mensajero/metabolismo , Transcriptoma , Adenosina/metabolismo , Animales , Línea Celular , Perfilación de la Expresión Génica , Regulación Viral de la Expresión Génica , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/virología , Herpesvirus Humano 8/crecimiento & desarrollo , Herpesvirus Humano 8/metabolismo , Humanos , Estadios del Ciclo de Vida , Procesamiento Postranscripcional del ARN , Proteínas Virales/genética , Proteínas Virales/metabolismo , Activación Viral , Latencia del Virus , Replicación ViralRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is one of the most aggressive non-Hodgkin lymphomas. It is curable but one-third of cases are refractory to therapy or relapse after initial response highlighting the urgent need for developing novel therapeutic approaches. Targeting sirtuins, particularly SIRT1 by genetic approaches or using pharmaceutical inhibitor tenovin-6, has shown promising therapeutic potential in various hematopoietic malignancies. However, it remains unknown whether these approaches are effective for DLBCL. In this study, we have found that tenovin-6 potently inhibits the proliferation and survival of DLBCL cells. Surprisingly, specific knockdown of SIRT1/2/3 has no effect on DLBCL. Mechanistically, tenovin-6 increases the level of microtubule-associated protein 1 light chain 3B (LC3B)-II in a SIRT1/2/3- and p53-independent manner in DLBCL cell lines. Tenovin-6-mediated increase of LC3B-II is through inhibition of classical autophagy pathway. Furthermore, inhibition of the autophagy pathway by using other inhibitors or by knocking down key genes in the pathway impairs cell proliferation and survival of DLBCL cells. These results indicate that targeting the autophagic pathway could be a novel therapeutic strategy for DLBCL and that precaution should be taken to interpret data where tenovin-6 was used as an inhibitor of sirtuins.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Benzamidas/farmacología , Biomarcadores de Tumor/metabolismo , Proliferación Celular/efectos de los fármacos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Asociadas a Microtúbulos/metabolismo , Antineoplásicos/farmacología , Humanos , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Células Tumorales CultivadasRESUMEN
Malignancies associated with Epstein-Barr virus (EBV) and/or Kaposi's sarcoma human herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is frequently found in patients infected with HIV. Both these human gammaherpesviruses are known for their oncogenic properties, for the viral products that mimic or interfere with the functions of critical cellular proteins, and the ability to escape the immune responses. The introduction of the highly active anti-retroviral therapy (HAART) has significantly decreased the frequency of Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and primary central nervous system lymphoma (PCNSL); conversely, for some lymphomas the incidence diminished only slightly, as in Burkitt's lymphoma (BL), or had no significant variations, as Hodgkin's lymphoma (HL). These observations may indicate that HAART might have a direct impact on KSHV and EBV biology, that there is a reconstitution of the immune system in HIV-infected patients under HAART, or even that HAART perhaps has a detrimental impact in the pathogenic interactions between HIV, EBV and KSHV. The present review aim to evaluate and to discuss the data available for these hypotheses, in order to shed more light on the mechanisms for the cooperation among HIV-1, EBV and KSHV that may culminate in cell transformation and cancer development in humans.
Asunto(s)
Regulación Viral de la Expresión Génica , VIH/metabolismo , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 8/metabolismo , Neoplasias/virología , Animales , Terapia Antirretroviral Altamente Activa , Linfocitos B/virología , Regulación Neoplásica de la Expresión Génica , Infecciones por VIH/virología , Humanos , Sistema Inmunológico , Ratones , Modelos Biológicos , Neoplasias/patología , Programas InformáticosRESUMEN
KSHV LANA1, a latent protein expressed during chronic infection to maintain a viral genome, inhibits major histocompatibility complex class I (MHC I) peptide presentation in cis as a means of immune evasion. Through deletional cloning, we localized this function to the LANA1 central repeat 1 (CR1) subregion. Other CR subregions retard LANA1 translation and proteasomal processing but do not markedly inhibit LANA1 peptide processing by MHC I. Inhibition of proteasomal processing ablates LANA1 peptide presentation. Direct expression of LANA1 within the endoplasmic reticulum (ER) overcomes CR1 inhibition suggesting that CR1 acts prior to translocation of cytoplasmic peptides into the ER. By physically separating CR1 from other subdomains, we show that LANA1 evades MHC I peptide processing by a mechanism distinct from other herpesviruses including Epstein-Barr virus (EBV). Although LANA1 and EBV EBNA1 are functionally similar, they appear to use different mechanisms to evade host cytotoxic T lymphocyte surveillance.
Asunto(s)
Presentación de Antígeno , Antígenos Virales/inmunología , Herpesvirus Humano 8/inmunología , Herpesvirus Humano 8/patogenicidad , Antígenos de Histocompatibilidad Clase I/inmunología , Evasión Inmune , Proteínas Nucleares/inmunología , Factores de Virulencia/inmunología , Antígenos Virales/metabolismo , Línea Celular , Clonación Molecular , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Eliminación de Secuencia , Factores de Virulencia/metabolismoRESUMEN
Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8 [HHV8]) and Epstein-Barr virus (EBV/HHV4) are distantly related gammaherpesviruses causing tumors in humans. KSHV latency-associated nuclear antigen 1 (LANA1) is functionally similar to the EBV nuclear antigen-1 (EBNA1) protein expressed during viral latency, although they have no amino acid similarities. EBNA1 escapes cytotoxic lymphocyte (CTL) antigen processing by inhibiting its own proteosomal degradation and retarding its own synthesis to reduce defective ribosomal product processing. We show here that the LANA1 QED-rich central repeat (CR) region, particularly the CR2CR3 subdomain, also retards LANA1 synthesis and markedly enhances LANA1 stability in vitro and in vivo. LANA1 isoforms have half-lives greater than 24 h, and fusion of the LANA1 CR2CR3 domain to a destabilized heterologous protein markedly decreases protein turnover. Unlike EBNA1, the LANA1 CR2CR3 subdomain retards translation regardless of whether it is fused to the 5' or 3' end of a heterologous gene construct. Manipulation of sequence order, orientation, and composition of the CR2 and CR3 subdomains suggests that specific peptide sequences rather than RNA structures are responsible for synthesis retardation. Although mechanistic differences exist between LANA1 and EBNA1, the primary structures of both proteins have evolved to minimize provoking CTL immune responses. Simple strategies to eliminate these viral inhibitory regions may markedly improve vaccine effectiveness by maximizing CTL responses.