Sendai virus trailer RNA binds TIAR, a cellular protein involved in virus-induced apoptosis

Abstract

Sendai virus (SeV) leader (le) and trailer (tr) RNAs are short transcripts generated during abortive antigenome and genome synthesis, respectively. Recombinant SeV (rSeV) that express tr-like RNAs from the leader region are non-cytopathic and, moreover, prevent wild-type SeV from inducing apoptosis in mixed infections. These rSeV thus appear to have gained a function. Here we report that tr RNA binds to a cellular protein with many links to apoptosis (TIAR) via the AU-rich sequence 5¢ UUUUAAAUUUU. Duplication of this AU-rich sequence alone within the le RNA confers TIAR binding on this le* RNA and a non-cytopathic phenotype to these rSeV in cell culture. Transgenic overexpression of TIAR during SeV infection promotes apoptosis and reverses the anti-apoptotic effects of le* RNA expression. Moreover, TIAR overexpression and SeV infection act synergistically to induce apoptosis. These short viral RNAs may act by sequestering TIAR, a multivalent RNA recognition motif (RRM) family RNA-binding protein involved in SeV-induced apoptosis. In this view, tr RNA is not simply a by-product of abortive genome synthesis, but is also an antigenome transcript that modulates the cellular antiviral response.

IRF-3 Activation by Sendai Virus Infection Is Required for Cellular Apoptosis and Avoidance of Persistence

“…It is clear that viral gene expression is required for triggering the rapid apoptosis, because UV inactivation of the infectious virions blocked this effect. We did not investigate the nature of the viral gene product responsible for the rapid apoptosis, but there is information in the literature regarding how the viral gene product, trailer RNA (trRNA), negatively regulates apoptosis (13). The SeV trRNAs are short transcripts generated during abortive gene replication (13).…”

“…We did not investigate the nature of the viral gene product responsible for the rapid apoptosis, but there is information in the literature regarding how the viral gene product, trailer RNA (trRNA), negatively regulates apoptosis (13). The SeV trRNAs are short transcripts generated during abortive gene replication (13). Viral apoptosis is blocked by trRNA, which sequesters a cellular proapoptotic RNA-binding protein, TIAR.…”

“…However, viral mutants have been generated that can establish persistent infection. One such mutant contains the L1618V mutation in the L protein (13). Other temperature-sensitive mutants, which can establish persistent infection, have mutations in the M and HN proteins (13) or the P protein (13).…”

“…One such mutant contains the L1618V mutation in the L protein (13). Other temperature-sensitive mutants, which can establish persistent infection, have mutations in the M and HN proteins (13) or the P protein (13). The reciprocal situation, in which wild-type SeV causes either apoptosis or persistent infection in the same cell line, has not been reported in the literature.…”

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

“…Notable splicing substrates for TIA-1/ TIAR are Fas (discussed above) and the epithelial-specific exon IIIb in the fibroblast growth factor receptor 2 (FGFR2) pre-mRNA, which is frequently excluded during cancer progression (Del Gatto-Konczak et al 2000;see below). Consistent with the fact that TIA-1/TIAR can promote production of the proapoptotic form of Fas, introduction of TIA-1/TIAR into cells promotes apoptosis (Tian et al 1991;Iseni et al 2002). In addition to their proapoptotic effects, TIA-1/TIAR depletion in HeLa cells was shown to result in increased proliferation (Reyes et al 2009).…”