Aichi virus 3C protease modulates LC3- and SQSTM1/p62-involved antiviral response

• Published in: Theranostics Vol. 10; no. 20; pp. 9200 - 9213
• Main Authors: Kung, Ming-Hsiang, Lin, You-Sheng, Chang, Tsung-Hsien
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2020; Ivyspring International Publisher
• Subjects: 3C Viral Proteases - metabolism; A549 Cells; Animals; Antibodies; Antiviral Agents - metabolism; Autophagy; Autophagy - physiology; Cell Line; Cell Line, Tumor; Chlorocebus aethiops; Cloning; Cytokines; Down-Regulation - physiology; Genomes; HEK293 Cells; Humans; Infections; Kinases; Kobuvirus - metabolism; Microtubule-Associated Proteins - metabolism; Plasmids; Protein expression; Proteins; Research Paper; Sequestosome-1 Protein - metabolism; Vero Cells; Viral infections; Viral Proteins - metabolism; Virus Replication - physiology; Viruses; St Louis Missouri; United States > US; Taiwan; LC3; antiviral inflammation; p62; Autophagy flux; picornavirus
• DOI: 10.7150/thno.47077
• ISSN: 1838-7640

Autophagy is an essential, homeostatic process by which cells break down their own components, it also contributes to restricting bacterial infection in host defense systems; yet, how autophagy regulates viral infection remains inconclusive. Aichi virus (AiV), belonging to the genus Kobuvirus in the family, causes acute gastroenteritis in human. The role of autophagy-mediated anti-viral activity on AiV infection was investigated in this study. The effect of autophagy-associated molecules in retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) antiviral signal axis was analyzed in AiV infected cells by using biochemistry and pharmacologic approaches. In addition, the AiV viral protein regulating autophagy-associated RLR activity was also evaluated. : In AiV-infected cells, autophagic flux including the formation of autophagic vacuoles, as well as degradation of microtubule-associated protein light chain 3 (LC3) and sequestosome-1 (SQSTM1/p62) were observed. Ectopic overexpression of LC3 and p62, but not Atg proteins, contributed to RLR antiviral signal axis, shRNA knockdown of LC3 and p62 led to a downregulation of antiviral inflammation. Moreover, AiV infection inhibited double-stranded RNA (dsRNA)-activated RLR activity by the viral protein 3C protease but not H42D, C143S protease dead mutants. AiV 3C protease caused the degradation of LC3 and p62, and also RLR signal proteins. This study reveals a possible mechanism of autophagy-associated proteins regulating virus replication. Maintaining a cellular level of LC3 and p62 during the viral infection period might help restrict virus replication. Although, AiV 3C protease dampens the LC3 and p62-mediated host antiviral machinery for AiV replication. Results obtained provide a better understanding of the molecular pathogenesis of AiV for developing methods of prevention and treatment.