ยฉ 2015, Wuhan Institute of Virology, CAS and Springer-Verlag Berlin Heidelberg. Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes eight accessory proteins, the functions of which are not yet fully understood. SARS-CoV protein 6 (P6) is one of the previously studied accessory proteins that have been documented to enhance viral replication and suppress host interferon (IFN) signaling pathways. Through yeast two-hybrid screening, we identified eight potential cellular P6-interacting proteins from a human spleen cDNA library. For further investigation, we targeted the IFN signaling pathway-mediating protein, N-Myc (and STAT) interactor (Nmi). Its interaction with P6 was confirmed within cells. The results showed that P6 can promote the ubiquitin-dependent proteosomal degradation of Nmi. This study revealed a new mechanism of SARS-CoV P6 in limiting the IFN signaling to promote SARS-CoV survival in host cells.