Severe acute respiratory syndrome coronavirus type 1(SARS-CoV-1) 1a-encoded papain-like protease (PLPro or nsp3) is primarily involved in SARS-CoV-1 replication. In addition, viral nsp3 is thought to remove ubiquitin (Ub) and ISG15 proteins from host cell proteins by recognizing a consensus motif LXGG (Lindner HA et al. 2005; Barretto N et al. 2005; Ratia K et al. 2006). As a de-ubiquitinating/de-ISGylating enzyme, viral nsp3 antagonizes host type I interferon (IFN) responses by blocking signal transducers and mediators (Lindner HA et al. 2005; Barretto N et al. 2005; Ratia K et al. 2006; reviewed in Báez-Santos YM et al. 2014). Dual luciferase reporters, western blotting and real-time PCR assays showed suppressed activation of transcription factors IRF-3, NF-κB and AP-1 in nsp3-expressing human promonocyte cells treated with imiquimod (IMQ), a TLR7 ligand (Li SW et al. 2016). Western blot analysis with anti-Lys48 and anti-Lys63 ubiquitin antibodies showed that PLPro (nsp3) removed Lys63-linked ubiquitin chains of TRAF3 and TRAF6, but not Lys48-linked ubiquitin chains in untreated and treated cells (Li SW et al. 2016). Thus, SARS-CoV-1 nsp3 is thought to inhibit TLR7-mediated cytokine production through removing Lys63-linked polyubiquitin chains of TRAF3/TRAF6.