Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin (Ub) ligases, with many members having important roles in innate immunity. TRIM21 is a cytosolic antibody receptor that recognizes the Fc portion of antibodies bound to incoming virions. On binding to these immune complexes, TRIM21 triggers the catastrophic disassembly of viral capsids at the proteasome, terminating viral infection. Simultaneously, TRIM21 "senses" the presence of the virus and provokes signaling cascades that activate the transcription factor NF-κB, ultimately alerting surrounding cells to the infection. Here, we uncover the stepwise ubiquitination mechanism catalyzed by TRIM21, as well as the various cofactors required, that allows these two antiviral activities to occur synchronously at the proteasome.