Ubiquitination requires a ubiquitin-activating enzyme, a ubiquitin-conjugating enzyme, and usually a substrate-specific ubiquitin-protein ligase. Multiubiquitination needs a fourth factor, to bind to the ubiquitin moieties of preformed conjugates and catalyze ubiquitin chain assembly in conjunction with the first three proteins.1 Human protein KIAA0126, with a predicted 1,073 amino acid residues, is a member of the novel protein family defined by ubiquitination conjugation factor E4.2 In yeast, E4 activity is linked to cell survival under stress conditions, indicating that eucaryotes use E4-dependent proteolysis pathways for multiple cellular functions.