The ZNF451 family, a novel class of SUMO enzymes

Lab Pichler

We discovered a novel family of SUMO conjugating enzymes with E3 ligase and E4 elongase (specialized E3s for SUMO chain elongation) functions (Figure 1, upper panel). We show that ZNF451 has SUMO E3 ligase activity and efficiently assembles SUMO2/3 chains. Detailed biochemical analysis demonstrates that ZNF451 functions distinct to all known E3 ligases described for SUMO and ubiquitin conjugation: ZNF451 executes catalysis via a tandem-SIM and its interSIM region.

One SIM orients the donor-SUMO, while a second SIM binds SUMO on the backside of the E2 enzyme. Intriguingly, this short tandem-SIM region is sufficient to extend a backside-anchored SUMO chain (E4 elongase activity) in contrast to chain initiation, which in addition requires a zinc finger region to recruit the initial acceptor SUMO (E3 ligase activity, Figure 1, lower left panel). Four human proteins share this E4-elongase activity (Figure 1, lower right panel) and are involved in stress-induced global sumo(2,3)ylation after DNA double strand break induction or proteasome inhibition in vivo (Eisenhardt, Chaugule et al 2015 and Cappadocia et al 2015).

We identified novel substrates for the ZNF451#1 upon stress stimulation and are currently investigating selected candidates to gain insights into ZNF451#1’s biological function, activation and substrate specificity.

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