潜伏感染神经系统中表达的BOHV-1蛋白能促进神经突出芽.pdf

A Bovine Herpesvirus 1 Protein Expressed in Latently Infected Neurons (ORF2) Promotes Neurite Sprouting in the Presence of Activated Notch1 or Notch3 Devis Sinani, Leticia Frizzo da Silva, Clinton Jones School of Veterinary Medicine and Biomedical Sciences, Nebraska Center for Virology, University of Nebraska—Lincoln, Lincoln, Nebraska, USA Bovine herpesvirus 1 (BHV-1) infection induces clinical symptoms in the upper respiratory tract, inhibits immune responses, and can lead to life-threatening secondary bacterial infections. Following acute infection, BHV-1 establishes latency in sensory neurons within trigeminal ganglia, but stress can induce reactivation from latency. The latency-related (LR) RNA is the only viral transcript abundantly expressed in latently infected sensory neurons. An LR mutant virus with stop codons at the amino termi- nus of the first open reading frame (ORF) in the LR gene (ORF2) is not reactivated from latency, in part because it induces higher levels of apoptosis in infected neurons. ORF2 inhibits apoptosis in transiently transfected cells, suggesting that it plays a crucial role in the latency-reactivation cycle. ORF2 also interacts with Notch1 or Notch3 and inhibits its ability to trans activate certain viral promoters. Notch3 RNA and protein levels are increased during reactivation from latency, suggesting that Notch may pro- mote reactivation. Activated Notch signaling interferes with neuronal differentiation, in part because neurite and axon genera- tion is blocked. In this study, we demonstrated that ORF2 promotes neurite formation in mouse neuroblastoma cells overex- pressing Notch1 or Notch3. ORF2 also interfered with Notch-mediated trans activation of the promoter that regulates the expression of Hairy Enhancer of Split 5, an inhibitor of neurite formation. Additional studies provided evidence that ORF2 pro- motes the degradation of Notch3, but not that of Notch1, in a proteasome-dependent manner. In summary, thes