Autophagy in Antiviral Immunity
Orvedahl, Anthony Walter
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Autophagy is an evolutionarily conserved pathway in which cytoplasmic material is sequestered in a double-membrane vesicle and delivered to the lysosome for degradation. During times of stress, autophagy functions to generate essential nutrients through the degradation of non-essential cytoplasmic contents. It is also the only known mechanism for removal of damaged or superfluous organelles and cytoplasmic contents that are too large to be degraded by the proteasome. Given the critical role for autophagy in stress response and in maintaining cell cytoplasmic quality control, it is not surprising that autophagy plays an essential role in the host response to infection, and that microbes have evolved mechanisms to counteract or evade autophagy. In this work, we studied the role of autophagy inhibition in a mouse model of herpes simplex virus type I (HSV-1) encephalitis, investigated the role of autophagy in protection against Sindbis virus infection of the central nervous system, and identified novel host genes involved in targeting viral proteins to the autophagy pathway. We found that the HSV-1 encoded neurovirulence protein ICP34.5 interacted with the host autophagy protein Beclin 1, and that this interaction was essential for HSV-1 neurovirulence. This was the first example of a viral virulence protein that targets host autophagy, and provided evidence that autophagy functions in innate immunity to viruses. In the second study, we found that the host autophagy gene Atg5 was required to protect against lethal Sindbis virus CNS diseases, and that autophagy targeted viral proteins for degradation in brains of infected mice and cells in vitro. We found that the autophagy adaptor protein p62 was involved in targeting viral proteins for autophagic degradation and this promoted survival of infected cells. This study demonstrated that clearance of viral proteins by autophagy was an important mechanism for cellular and organismal survival during viral infection. Lastly, we performed a genome-wide siRNA screen to identify novel host factors required for autophagic targeting of viral proteins. We identified previously unappreciated cellular networks and genes that were involved in targeting viral proteins for autophagy. One of these factors, SMURF1, is an E3 ubiquitin ligase that not only functions to target viral proteins, but is also involved in targeting damaged mitochondria for autophagic clearance.