The dynein light chain 8 binding motif of rabies virus phosphoprotein promotes efficient viral transcription.
Recent studies indicate that the interaction between rabies virus (RV) phosphoprotein and the dynein light chain 8 (LC8) is essential for RV pathogenesis. Through its association with the dynein motor complex, LC8 has been suggested as a molecular factor that links the viral ribonucleoprotein to the host cell transport system. Recent structural investigations, however, dispute this model. To understand the role of LC8 in RV pathogenesis, we generated recombinant RVs with or without the LC8 binding domain (LC8-BD) deleted from the RV phosphoprotein. Peripheral infection of adult mice showed that removal of the LC8-BD did not inhibit entry into the CNS, although it prevented onset of RV-induced CNS disease. However, deletion of the LC8-BD significantly attenuated viral transcription and replication in the CNS. Studies in RAG2 knockout (KO) mice infected with the same recombinant RVs confirmed this finding and indicated that the adaptive immune system is not a factor in the attenuation of viral replication early in the infection. In cell culture, the deletion of the LC8-BD greatly attenuated growth on neuronal cells whereas the growth pattern on nonneuronal cells remained unchanged. However, deletion of the LC8-BD did not affect production of RV virions. We provide evidence that removal of the LC8-BD decreases primary transcription. In this study, we propose that LC8 does not play a role in the retrograde axonal transport of RV and that the deletion of the LC8-BD impairs the infectivity of the virions by reducing early transcription and replication in neurons.
Tan
Gene S
GS
Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107-5541, USA.
Preuss
Mirjam A R
MA
Williams
John C
JC
Schnell
Matthias J
MJ
D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D002490:Central Nervous System / Q000821:virology; D004398:Dyneins / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000821:virology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D011818:Rabies / Q000517:prevention & control; D011820:Rabies virus / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000096:biosynthesis / Q000737:chemistry*; D053586:Virus Internalization; D014779:Virus Replication
D006023:Glycoproteins; D010750:Phosphoproteins; D012367:RNA, Viral; D014764:Viral Proteins; D004398:Dyneins