Figure 1.

Canonical and non-canonical mechanisms of EBV-mediated host shutoff. (A) Canonical EBV host shutoff occurs in the cytoplasm via a two-step process: initial endonucleolytic cleavage by BGLF5 and subsequent degradation by cellular exonucleases (Xrn1, Dis3L2, and likely the exosome complex (not shown)). mRNA degradation releases RNA binding proteins (RBPs), which are recycled into the nucleus. The accumulation of RBPs, in particular the cytoplasmic poly(A)-binding protein (PABPC), induces a state of cellular stress that inhibits host gene expression by inhibiting transcription by RNA polymerase II and possibly by suppressing the nuclear export of mRNAs. (B–D) Non-canonical EBV host shutoff mechanisms include: (B) global loss of host chromatin accessibility induced by the immediate early protein Zta. (C) During the late phase of replication, host chromatin compaction occurs in parallel with the expansion of viral replication compartments that is believed to further disrupt the ability of the host cell to express its gene repertoire. (D) Preferential export of non-spliced viral mRNA mediated by the EBV SM protein. Abbreviations: NLS, nuclear localization signals; CBC, cap-binding complex; TF, transcription factor. Figure created with BioRender.com.