Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 297, Issue 5, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.101190
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Funding
- Gansu major science and technology projects [20ZD7NA006]
- National Key Research and Development Program [2018YFC0840402]
- National Natural Science Foundation of China [31941002]
- Special Fund for Basic Scientific Research of Chinese Academy of Agricultural Sciences [Y2019YJ07-01]
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This study elucidates the mechanism by which the ASFV-encoded protein MGF-505-7R inhibits the JAK-STAT1 signaling pathway, resulting in reduced replication capacity of ASFV in the host. Deletion of MGF-505-7R attenuates the virulence and pathogenesis of ASFV, suggesting its potential as a strategy for developing vaccines against ASFV.
African swine fever virus (ASFV) is a large DNA virus that is highly contagious and pathogenic in domestic pigs with a mortality rate up to 100%. However, how ASFV suppresses JAK-STAT1 signaling to evade the immune response remains unclear. In this study, we found that the ASFV-encoded protein MGF-505-7R inhibited proinflammatory IFN-gamma-mediated JAK-STAT1 signaling. Mechanistically, MGF-505-7R was found to interact with JAK1 and JAK2 and mediate their degradation. Further study indicated that MGF-505-7R promoted degradation of JAK1 and JAK2 by upregulating the E3 ubiquitin ligase RNF125 expression and inhibiting expression of Hes5, respectively. Consistently, MGF-505-7R-deficient ASFV induced high levels of IRF1 expression and displayed compromised replication both in primary porcine alveolar macrophages and pigs compared with wild-type ASFV. Furthermore, MGF-505-7R deficiency attenuated the virulence of the ASFV and pathogenesis of ASF in pigs. These findings suggest that the JAK-STAT1 axis mediates the innate immune response to the ASFV and that MGF-505-7R plays a critical role in the virulence of the ASFV and pathogenesis of ASF by antagonizing this axis. Thus, we conclude that deletion of MGF-505-7R may serve as a strategy to develop attenuated vaccines against the ASFV.
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