RIP2 induces the K63-linked ubiquitination of NEMO at K285 and K399, positively modulating subsequent NF-kappaB activation (Abbot et al. 2007). TRAF6 E3 ligase is capable of performing this ubiquitination step when overexpressed in HEK239 cells, and this effect is blocked if RIP2 siRNA is co-transfected, but small interfering RNA (siRNA) experiments indicate that there are additional E3 ligases that can substitute for TRAF6 in NEMO ubiquitination. In addition to TRAF6, the K63-specific E2 ligase Ubc13 is required for NEMO ubiquitination suggesting a common mechanism for NEMO ubiquitination in NOD and TLR signaling.