USP14 and bilirubin encephalopathy: UCB is a known neurotoxin; at abnormally high concentrations, it can cause permanent neurological damage in neonates.22, 23, 24, 25 Here we demonstrate for the first time that bilirubin can effectively inhibit proteasomal function through both direct inhibition of 19S proteasome-associated DUBs (USP14 and UCHL5) and suppressing 20S proteasome peptidase activity and that elevated levels of serum bilirubin are capable of suppressing proteasomal protein degradation in neurons in vitro and in vivo, providing a novel pathogenic mechanism for neonatal bilirubin encephalopathy.