Changes in Cellular mRNA Stability, Splicing, and Polyadenylation through HuR Protein Sequestration by a Cytoplasmic RNA Virus

Abstract

Summary The impact of RNA viruses on the post-transcriptional regulation of cellular gene expression is unclear. Sindbis virus causes a dramatic relocalization of the cellular HuR protein from the nucleus to the cytoplasm in infected cells. This is due to the expression of large amounts of viral RNAs that contain high affinity HuR binding sites in their 3’ UTRs effectively serving as a sponge for the HuR protein. Sequestration of HuR by Sindbis virus is associated with destabilization of cellular mRNAs that normally bind HuR and rely on it to regulate their expression. Furthermore, significant changes can be observed in nuclear alternative polyadenylation and splicing events on cellular pre-mRNAs due to sequestration of HuR protein by the 3’ UTR of transcripts of this cytoplasmic RNA virus. These studies suggest a new molecular mechanism of virus-host interaction that likely has significant impact on virus replication, cytopathology and pathogenesis.

Connections between 3′ end processing and DNA damage response: Ten years later

“…Some of those transcripts include proto‐oncogenes c‐Fos (C. Y. Chen, Xu, & Shyu, ) and c‐Myc (Gunzburg et al, ); cyclooxygenase‐2 (COX‐2; Doller et al, ); iNOS (Z. Guo & Geller, ); tumor suppressors TP53 (Abdelmohsen et al, ) and von Hippel–Lindau (Galbán et al, ). Interestingly, HuR can also regulate APA of target genes dependent on U‐rich sequences proximal to poly(A) signal (Barnhart, Moon, Emch, Wilusz, & Wilusz, ; Berkovits & Mayr, ; Zhu, Zhou, Hasman, & Lou, ), of genes involved in stress responses (Kraynik et al, ), and of its own gene through reduction of CstF‐64 recruitment (Dai, Zhang, & Makeyev, ).…”

Determinants and implications of mRNA poly(A) tail size – Does this protein make my tail look big?

“…Specific mRNAs destined to serve as primary-miRNA precursors in the nucleus that are subject to DROSHA processing also may not necessarily need a significant poly(A) tail. Other possible functions of mRNAs with short poly(A) tails include acting as RNA scaffolds, targeting other transcripts for trans-regulation by staufen-mediated decay [113] and other processes [114] and by behaving as RNA-based protein sponges [115]. Clearly there may be a large potential for novel insights into gene regulation by additional experimentation in the area of poly(A) tail dynamics.…”

Viral Manipulation of Host Mrna Decay

“…Other examples of virus interacting with AREBPs are alphaviruses, including sindbis virus, ross river virus and chikungunya virus [15,16]. The 3′ UTRs of sindbis virus RNAs bind to HuR with high affinity, which causes the relocation of HuR from the nucleus to the cytoplasm and the sequestration of HuR in the cytoplasm.…”

“…The 3′ UTRs of sindbis virus RNAs bind to HuR with high affinity, which causes the relocation of HuR from the nucleus to the cytoplasm and the sequestration of HuR in the cytoplasm. These changes are associated with the destabilization of cellular mRNAs that are normally targeted by HuR [15].…”

“…Interact with ARE binding proteins HSV, adenovirus, alphaviruses, coxsackievirus B3 and EBV [12][13][14][15][16][17][18][19] Activate signaling pathways to affect ARE or GRE binding proteins KHSV, HSV1 and HCV [20][21][22][23][24][25][26] Viral protein binds to GRE HCV [27] mRNA surveillance pathway…”