RESUMEN
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.
Asunto(s)
Herpesvirus Humano 8 , Proteínas Inmediatas-Precoces , Proteolisis , Transactivadores , Factores de Transcripción , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Activación Viral , Replicación Viral , Humanos , Apoptosis , Línea Celular , Herpesvirus Humano 8/crecimiento & desarrollo , Herpesvirus Humano 8/metabolismo , Herpesvirus Humano 8/patogenicidad , Herpesvirus Humano 8/fisiología , Proteínas Inmediatas-Precoces/metabolismo , Proteínas Inmediatas-Precoces/genética , Linfoma de Efusión Primaria/virología , Linfoma de Efusión Primaria/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Sarcoma de Kaposi/virología , Sarcoma de Kaposi/metabolismo , Transactivadores/metabolismo , Transactivadores/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Latencia del VirusRESUMEN
IMPORTANCE: The development of broad-spectrum SARS-CoV-2 vaccines will reduce the global economic and public health stress from the COVID-19 pandemic. The use of conserved T-cell epitopes in combination with spike antigen that induce humoral and cellular immune responses simultaneously may be a promising strategy to further enhance the broad spectrum of COVID-19 vaccine candidates. Moreover, this research suggests that the combined vaccination strategies have the ability to induce both effective systemic and mucosal immunity, which may represent promising strategies for maximizing the protective efficacy of respiratory virus vaccines.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Vacunas Combinadas , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunidad Celular , Inmunización , Pandemias/prevención & control , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , VacunaciónRESUMEN
Background: Lactate is associated with the poor prognosis of many human malignancies. Cervical cancer, one of main causes of women mortality worldwide, is aggressive and absent of effective pharmacological treatment, and its underlying mechanisms of progression remain elusive. Methods: The regulation of ß-catenin to fascin protrusion formation upon acidic lactate (Lactic acid [LA]) stimulation was evaluated through in ß-catenin or fascin deficiency cell line models by immunofluorescence assays, and subcellular fractionation. The effect of ß-catenin and fascin relocation by LA and its antagonist were evaluated by immunohistochemistry assay in patient tissues and mouse tumor xenograft model. Trypsin digestion, Transwell assay, cell proliferation in vitro was performed to explore the role of LA in the cell growth, adhesion and migration. Results: Low concentration of LA significantly promotes cytoskeleton remodeling via `protrusion formation to increase cell adhesion and migration. Mechanistically, upon LA stimulation, ß-catenin diffuses from the cytoplasmic membrane into the nucleus, which in turn induces fascin nuclear-cytoplasm redistribution to the protrusion compartment. Moreover, the antagonist of LA sufficiently blocks the LA-mediated ß-catenin nuclear import, fascin nuclear export, and the growth and invasion of cervical cancer cells in vitro and in vivo using a murine xenograft model. Conclusions: This study uncovers ß-catenin-fascin axis as a key signal in response to extracellular lactate and indicates that antagonist of LA may serve as a potential clinical intervention for cancer development.