Ubiquitin's duality

Ubiquitin does more than mark proteins for degradation. In 2004, Ingrid Wertz, a University of California, Davis graduate student, and advisor Vishva Dixit of Genentech, demonstrated that the protein A20, which was known to downregulate tumor necrosis factor á (TNFá) signaling, has both an ubiquitin ligase domain and a deubiquitinating domain.1 Wertz, now at the University of Washington, St. Louis, says she found the presence of these opposing functions disconcerting: "I was thinking, h

Jul 1, 2006
Karyn Hede

Ubiquitin does more than mark proteins for degradation. In 2004, Ingrid Wertz, a University of California, Davis graduate student, and advisor Vishva Dixit of Genentech, demonstrated that the protein A20, which was known to downregulate tumor necrosis factor á (TNFá) signaling, has both an ubiquitin ligase domain and a deubiquitinating domain.1 Wertz, now at the University of Washington, St. Louis, says she found the presence of these opposing functions disconcerting: "I was thinking, how could a deubiquitinase downregulate TNF receptor signaling? And then it all came together very clearly when I realized that our antibodies were not distinguishing between the K48 polyubiquitination versus the K63 polyubiquitination."

Indeed, A20 delivers a one-two punch to the regulatory protein RIP, first removing the activating K63 ubiquitination, then polyubiquitinating K48, marking the protein for degradation, effectively attenuating TNFá-induced NFêB signaling. "[The paper] identified a major step in NFêB signaling; it revealed a role for ubiquitin chain editing, as opposed to simple ubiquitination; and it identified the A20 zinc finger domain as a new structural class of ubiquitin ligase," says James Hurley, a protein crystallographer at the National Institutes of Health, who recently confirmed A20's unique structure and mechanism.

The discovery underscores the importance of ubiquitination, which acts as a brake for proliferation signals, according to Dixit. "If you remove that brake," he says, "you're in big trouble."

References

1. I.E. Wertz et al., "De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-ê B signaling" Nature, 430:694-9, 2004. (Cited in 81 papers).