RIG-I is an innate pattern-recognition receptor that senses viral RNA. The activation and signal transduction of RIG-I involves modification by addition of Lys63-linked polyubiquitin chains, but how this activation pathway is terminated to prevent excessive inflammatory responses is unclear. In the Journal of Experimental Medicine, Fan et al. identify the deubiquitinase USP21 as a critical regulator of RIG-I signaling. USP21 can constitutively associate with RIG-I and functions to directly remove Lys63-linked ubiquitin moieties from both RIG-I and the cytosolic receptor Mda5. Overexpression of USP21 blocks the generation of antiviral responses. Conversely, deletion of USP21 leads to enhanced RIG-I-mediated activation of the transcription factors IRF3 and NF-κB and the resultant expression of type I interferons. Mice that lack USP21 have enhanced antiviral activity but at the expense of the development of splenomegaly. Thus, USP21 seems to be a physiologically relevant regulator of RIG-I function in response to viral infection.

J. Exp. Med. 211, 313–328 (2014)