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The viral lncRNA LMP2A-IT1 promotes Epstein-Barr virus lytic replication

ABSTRACT: The Epstein-Barr virus (EBV) employs lytic replication to facilitate viral propagation and pathogenesis; however, the regulatory mechanisms governing this process remain incompletely elucidated. Here, we identify LMP2A-IT1, a novel 276-nt RNA derived from the first intron of the LMP2A gene. This transcript directly interacts with the nuclear export factor exportin 5 (XPO5) and exhibits predominant cytoplasmic localization. Functionally, LMP2A-IT1 expression is markedly upregulated during EBV lytic reactivation and subsequently amplifies viral gene expression and DNA replication—a phenomenon further supported by the positive correlation between LMP2A-IT1 levels and EBV DNA copy numbers in human nasopharyngeal carcinoma tissues. Mechanistically, cytoplasmic LMP2A-IT1 likely activates inflammatory response, thereby upregulating the immediate-early transactivators BZLF1 and BRLF1 to initiate the EBV lytic cycle. Our study establishes LMP2A-IT1 as a novel EBV-encoded RNA and reveals its function as a key positive feedback regulator of EBV lytic replication. These findings provide new insights into EBV replication dynamics and underscore the functional significance of viral RNAs in EBV biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320354 | GEO | 2026/02/24

REPOSITORIES: GEO

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Project description:Abstract: Epstein-Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells sometimes cause B cell malignancies in humans with T- or NK-cell deficiency. We now find EBV-encoded Latent Membrane Protein 2A (LMP2A) to mimic B cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B cell differentiation in mice that conditionally express LMP2A in GC B cells, or all B-lineage cells, found LMP2A expression enhanced not only BCR signals but also plasma-cell differentiation, in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody–producing B-cells despite apparently normal GC formation. GC B cell-specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the Zbtb20 locus. We conclude that LMP2A reduces the stringency of GC B cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with pro-survival signals. Significance Statement: Epstein-Barr virus (EBV) is a human herpesvirus that establishes persistent infection of the B-cell compartment. EBV is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). However, the molecular mechanisms by which EBV contributes to autoimmunity remain unclear. We used transgenic mouse models to study the role of EBV-encoded Latent membrane protein 2A (LMP2A), which mimics B-cell receptor signaling.　Interestingly, LMP2A not only enhanced B-cell survival, but also upregulated the transcription factor Zbtb20 and promoted plasma cell differentiation. When expressed late in B-cell development, LMP2A also caused prominent features of SLE, including autoantibody production with kidney immune complex deposition. Our findings suggest that LMP2A has important roles in B cell activation, differentiation and the development of EBV-associated autoimmune diseases.

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The viral lncRNA LMP2A-IT1 promotes Epstein-Barr virus lytic replication

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