Severe acute respiratory syndrome coronavirus type 1 (SARS‑CoV‑1) open reading frame 3a (orf3a or 3a) protein activates the NLRP3 inflammasome in human cells (Siu KL et al. 2019). Viral 3a contains a tumor necrosis factor (TNF) receptor‑associated factor (TRAF)‑binding motif, PLQAS, located at aa 36‑40. The viral 3a protein was shown to interact with endogenous TRAF3 and Apoptosis‑associated Speck‑like protein containing a CARD (ASC, PYCARD) in 3a‑expressing human monocytic THP‑1 cells. Similar results were obtained in human embryonic kidney 293 (HEK293) cells ectopically expressing differentially tagged viral 3a, PYCARD (ASC) or TRAF3 proteins. In addition, orf3a colocalized with TRAF3 and ASC in discrete punctate structures in the cytoplasm of human lung adenocarcinoma A549 cells derived from alveolar basal epithelium (Siu KL et al. 2019). The data suggest that viral 3a promotes NLRP3 inflammasome activation by interaction with both TRAF3 and PYCARD (ASC) to facilitate TRAF3‑mediated K63‑linked polyubiquitination of PYCARD, leading to the formation of PYCARD (ASC) specks (Siu KL et al. 2019). In addition, 3a promoted TRAF3‑mediated ubiquitination of p105, leading to NF‑κappaB‑induced transcription of pro‑IL‑1β, and thus providing signal 1 for NLRP3 inflammasome activation (Siu KL et al. 2019).