X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency.
Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the B-cell neoplasm primary effusion lymphoma (PEL), in which the virus remains latent. We have previously shown that PEL cells have the gene expression profile and immunophenotype of cycling preplasma cells (plasmablasts). Here, we show that the highly active spliced isoform of plasma cell transcription factor X box binding protein 1 (XBP-1s) is a lytic switch for KSHV. XBP-1s is normally absent in PEL, but the induction of endoplasmic reticulum stress leads to XBP-1s generation, plasma cell-like differentiation, and lytic reactivation of KSHV. XBP-1s binds to and activates the KSHV immediate-early gene ORF50 and synergizes with the ORF50 gene product RTA to induce a full lytic cycle. These data suggest that KSHV remains latent until B-cell terminal differentiation into plasma cells, the transcriptional environment of which provides the physiological "lytic switch" through XBP-1s. This links B-cell terminal differentiation to KSHV lytic reactivation.
Wilson
Sam J
SJ
Department of Infection, UCL, 46 Cleveland Street, London W1T 4JF, United Kingdom.
Tsao
Edward H
EH
Webb
Benjamin L J
BL
Ye
Hongtao
H
Dalton-Griffin
Lucy
L
Tsantoulas
Christoforos
C
Gale
Catherine V
CV
Du
Ming-Qing
MQ
Whitehouse
Adrian
A
Kellam
Paul
P
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000166:cytology*; D011401:Promoter Regions, Genetic; D000071701:Regulatory Factor X Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D000071701:Regulatory Factor X Transcription Factors; C417604:Rta protein, Human herpesvirus 8; D015534:Trans-Activators; D014157:Transcription Factors; D014764:Viral Proteins; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human