Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

Brisse, Morgan; Ly, Hinh

Once the C terminal domains have been de-phosphorylated, the E3 ubiquitin ligase Riplet attaches ubiquitin peptides onto the C terminal domain of RIG-I at residues K849 and K851 (100, 101) . It was previously shown that ubiquitination by Riplet was necessary for opening RIG-I and for ubiquitination of the CARD domain (102) . However, in-situ studies found that dsRNA was sufficient to weaken the interaction between purified RIG-I C terminal domain and RIG-I CARD domains (86) and that dsRNA was necessary for Riplet ubiquitination (103) , calling into question the sequential order for RIG-I activation ( Figure 4C ). Following de-phosphorylation of the CARD domain by the phosphatase PP1-α/γ (92) , this domain is polyubiquinated at K172 by the E3 TRIM25 ubiquitin ligase (104) , which itself is activated by Caspase 12 (105) (Figure 4D ). TRIM25 interacting with RIG-I may also be mediated by their mutual interactions with certain host long non-coding RNA (lncRNA), which occurs outside of the dsRNA recognizing domain in the CTD of RIG-I (106) .