Optineurin deficiency impairs autophagy to cause interferon beta overproduction and increased survival of mice following viral infection
BackgroundOptineurin (OPTN) is associated with several human diseases, including amyotrophic lateral sclerosis (ALS), and is involved in various cellular processes, including autophagy. Optineurin regulates the expression of interferon beta (IFN{beta}), which plays a central role in the innate immune response to viral infection. However, the role of optineurin in response to viral infection has not been fully clarified. It is known that optineurin-deficient cells produce more IFN{beta} than wild-type cells following viral infection. In this study, we investigate the reasons for, and effects of, IFN{beta} overproduction during optineurin deficiency both in vitro and in vivo. MethodsTo investigate the mechanism of IFN{beta} overproduction, viral nucleic acids in infected cells were quantified by RT-qPCR and the autophagic activity of optineurin-deficient cells was determined to understand the basis for the intracellular accumulation of viral nucleic acids. Moreover, lethal viral infection experiments using optineurin-disrupted (Optn-KO) animals were performed. ResultsIFN{beta} overproduction following viral infection was observed not only in several types of optineurin-deficient cell lines but also in Optn-KO mice and human ALS patient cells carrying mutations in OPTN. IFN{beta} overproduction in Optn-KO cells was revealed to be caused by excessive accumulation of viral nucleic acids, which was a consequence of reduced autophagic activity caused by the loss of optineurin. Additionally, IFN{beta} overproduction in Optn-KO mice suppressed viral proliferation, resulting in increased mouse survival following lethal viral challenge. ConclusionOur findings indicate that the combination of optineurin deficiency and viral infection leads to IFN{beta} overproduction in vitro and in vivo. The effects of optineurin deficiency are elicited by viral infection, therefore, viral infection may be implicated in the development of optineurin-related diseases.