Our data suggest the following sequence of events: IFNs, released during infections, increase cellular ATP levels; RNF213 senses changes in ATP/ADP ratios via its AAA core, which regulates its atypical transthiolating E3 module; the E2~Ub docks onto RNF213 via the CTD, while the RZ domain provides the catalytic cysteine nucleophile required for transthiolation with E2~Ub; ubiquitin is transferred to Cys4462, forming the reactive acyl donor tasked with substrate modification; additional contacts between the E2 and the E3 shell, and Ub and the RZ domain, may optimize Ub transfer. The gene discussed is RNF213; the disease is infection.