Eukaryotic signaling has been likened to a code, written and read by modules catalyzing and binding post-translational modifications, respectively. The information transferred by this code ultimately determines the fate of virtually all cellular processes, from cell cycle regulation to metabolic pathways. Homologous modules often mediate signaling by parallel structural mechanisms. However, we discovered that structurally unique super-assemblies are formed between related but distinct modification targets (NEDD8-modified cullin-RING ligase E3s, CRLs) and their homologous readers (ARIH-family RBR E3s), which are ubiquitin writers for CRL-bound substrates. Modification of CUL5-RBX2 with the ubiquitin-like protein NEDD8 and “reading” by the ubiquitin writer ARIH2, was genetically-validated for its importance in pathological hijacking of CUL5 by HIV-1 1 . HIV-1 replication in host cells depends on usurping cellular UB-dependent proteasomal degradation pathways to degrade host immune proteins. HIV-1 virion infectivity factor (Vif), acting together with its conscripted host protein CBF, act as CRL5 substrate receptors mediating ubiquitylation of APOBEC3 family restriction factors2-4 . Surprisingly, studies found that the level of APOBEC3G and HIV-1 infectivity further depends on the presence of the RBR E3 ARIH2 and on the activation of CRL5 by NEDD8. These findings are consistent with results from previous studies where CRLs and ARIH E3 ligases have to work together to ubiquitylate substrates1,5,6 Here, our structures and biochemistry reveal distinctive autoinhibition and activation mechanisms of the ARIH RBR E3 ligase ARIH2. It is activated upon super-assembly into an E3-E3 ubiquitin ligase complex with HIV-1 Vif-hijacked neddylated CUL5-RBX2 and APOBEC3-family substrates. Comparison of neddylated CUL1-RBX1 superassemblies with ARIH1 shows NEDD8 uniquely contacts with its covalently-linked CUL5. While ARIH1 is directly recruited to the CUL1-linked NEDD8, CUL5-linked NEDD8 forms no direct contacts with ARIH2 but instead elicits large-scale structural rearrangements in CUL5 that expose cryptic ARIH2 binding sites. Our data reveal that 6 a UBL modification is read indirectly through allostery, which may offer routes for specifically targeting related UBL pathways including those hijacked by viruses.