In this preprint, Dominguez Andres et al. report that the viral protein ORF9c may be involved in immune evasion. They show that it is highly unstable and is the first human coronavirus ORF9c protein that appears to have acquired a transmembrane domain. When expressed in the human lung epithelial cell line A549, SARS-CoV-2 ORF9c interfered with interferon signalling, antigen presentation and other immune and stress pathways. Interestingly, inhibition of the proteasome or the ATPase VCP counteracted the effects of ORF9c expression. Although mechanistically unclear, the likely membrane localization of ORF9c and its links to the proteasome and VCP suggest it modulates endoplasmic reticulum-associated degradation. Further research is needed to understand the potential role of ORF9c in immune evasion.