Abstract
Severe cases of COVID-19 are associated with immune responses that lead to a surge in inflammatory molecules, resulting in multi-organ failure and death. This significant increase in inflammatory factors is triggered by viral proteins. Open reading frame 8 (ORF8) has received particular attention as a unique accessory protein of SARS-CoV-2. In a previous study, we have examined the role of unconventionally released ORF8 during cytokine storm associated with SARS-CoV-2 infection. Here, after mass spectrometry analysis and gene knockout/knockdown in cell/hamster models, we further discovered that Yip1 interacting factor homolog B (YIF1B) directly translocates unglycosylated ORF8 into vesicles that mediate cargo transport; specifically, the α4 helix of YIF1B interacts with the β8 sheet. Blocking ORF8 unconventional secretion via YIF1B knockdown attenuates inflammation and yields reduced mortality. Our study suggests that YIF1B directs ORF8 translocation into an unconventional secretion pathway, which has significant implications for the pathogenesis and treatment of COVID-19.