Host and virus interactions at the post-transcriptional level are critical for infection but remain poorly understood. Human cytomegalovirus (HCMV) is a prevalent herpesvirus family member that causes severe complications in immunocompromised patients and newborns. Here, we perform comprehensive transcriptome-wide analyses revealing that HCMV infection results in widespread alternative splicing (AS), shorter 3′-untranslated regions (3′UTRs) and polyA tail lengthening in host genes. The host RNA binding protein cytoplasmic polyadenylation element binding protein 1 (CPEB1) is highly induced upon infection and ectopic expression of CPEB1 in non-infected cells recapitulates infection-related post-transcriptional changes. CPEB1 is also required for polyA-tail lengthening of viral RNAs important for productive infection. Strikingly, depletion of CPEB1 reverses infection-related cytopathology and post-transcriptional changes, and decreases productive HCMV titers. Host RNA processing is also altered in herpes simplex virus-2 (HSV-2) infected cells, indicating a common theme among herpesvirus infections. Our work is a starting point for therapeutic targeting of host RNA binding proteins in herpesvirus infections.

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Recently we demonstrated that a member of the neuregulin-1 (NRG-1) family of growth factors is a mitogen and survival factor for olfactory ensheathing cells (OECs). OECs are specialized glial cells within the olfactory system that are believed to play a role in the continual nerve re-growth of this tissue. OECs share properties with both astrocytes and Schwann cells but are likely to be a distinct glial cell type. NRG-1s have been found to be important regulators of Schwann cells in vivo, but the role of NRG-1 for OECs is less clear. The nrg-1 gene produces at least 12 different isoforms, that are likely to have different functions, due to alternative splicing of its mRNA. In this study, the expression of NRG-1 mRNAs in OECs was compared with other glial cells and their corresponding tissue sources. Cultured glial cells, unlike their tissue sources, expressed NRG-1 mRNAs containing the alpha EGF-like domain and expressed only the type 1beta isoform that lacks the glycosylated spacer domain. This correlated with expression of these isoforms during olfactory nerve degeneration in vivo. Although OECs expressed mRNA for all NRG-1 isoforms, the protein could not be detected in concentrated supernatant, or on the cell surface by immunofluorescence, but was detected in the nucleus or cytoplasm (depending on the isoform). These data support the hypothesis that NRG-1s play a functional role in OEC biology.

Human cytomegalovirus (HCMV) is the main viral cause of birth defects, often leading to neurological disorders, but the underlying molecular mechanisms are poorly characterized. To advance our understanding of the complex virus‐host transcriptional landscape present during infection, we have completed a suite of comprehensive transcriptome‐focused studies using HCMV‐infected human fibroblasts and neural stem cells. Through deep sequencing analysis of small RNAs, we have refined viral miRNA annotations, identified novel HCMV miRNAs, and observed significantly upregulated host miRNAs. We also sequenced Argonaute‐associated RNAs (Ago CLIP‐seq) to obtain direct evidence for incorporation of all HCMV miRNAs into the endogenous host silencing machinery. High‐throughput sequencing of polyadenylated mRNAs (RNA‐seq) has enabled us to identify novel spliced HCMV transcripts and hundreds of human genes that are alternatively spliced upon infection. Our findings will enable the elucidation of improved therapeutic targets in the near future.This work was supported by grants from the U.S. National Institutes of Health (HG004659 and GM084317), the California Institute for Regenerative Medicine (RB3‐05219), and the Stem Cell Program at UCSD.