Abstract
Inflammation is essential for healthy immune function, wound healing, and resolution of infection. RIG-I is a key RNA sensor that initiates an immune response, with activation and termination of RIG-I signaling reliant on its modification with ubiquitin. The RING E3 ubiquitin ligase, RNF125, has a critical role in the attenuation of RIG-I signaling, yet it is not known how RNF125 promotes ubiquitin transfer or how its activity is regulated. Here we show that the E3 ligase activity of RNF125 relies on the first zinc finger (ZF1) as well as the RING domain. Surprisingly, ZF1 helps recruit the E2, while residues N-terminal to the RING domain appear to activate the E2∼Ub conjugate. These discoveries help explain how RNF125 brings about the termination of RIG-I dependent inflammatory responses, and help account for the contribution of RNF125 to disease. This study also reveals a new role for ZF domains in E3 ligases.
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•The E3 ligase RNF125 helps resolve immune responses by promoting degradation of RIG-I•RNF125 requires zinc finger 1 to promote assembly of ubiquitin chains•Zinc finger 1 of RNF125 contacts the E2 directly•Residues N-terminal to the RING domain stabilize the closed conformation of E2∼Ub
Inflammation is essential for immune function, but switching it off is also important. Here, Middleton et al. show that RNF125, an E3 ligase with an important role in quenching inflammation, requires both its RING and zinc-finger domains to recruit the ubiquitin machinery. This discovery helps explain how RNF125 regulates inflammation.