J. Neurochem. (2011) 116, 1160–1170.

Ubiquitin carboxyl‐terminal hydrolase L1 (UCH‐L1) is a deubiquitinating enzyme that plays a regulatory role in targeting proteins for proteasomal degradation. UCH‐L1 is highly expressed in neurons and has been demonstrated to promote cell viability and maintain neuronal integrity. Reduced UCH‐L1 levels have been observed in various neurodegenerative diseases, and expression of UCH‐L1 can rescue synaptic dysfunction and memory deficits in Alzheimer’s Disease model mice. However, the mechanisms regulating UCH‐L1 expression have not been determined. In this study, we cloned a 1782 bp of the 5′ flanking region of the human UCH‐L1 gene and identified a 43 bp fragment containing the transcription start site as the minimal region necessary for promoter activity. Sequence analysis revealed several putative regulatory elements including NF‐κB, NFAT, CREB, NRSF, YY1, AP1, and STAT in the UCH‐L1 promoter. A functional NF‐κB response element was identified in the UCH‐L1 promoter region. Expression of NF‐κB suppressed UCH‐L1 gene transcription. In the RelA knockout system where NF‐κB activity is ablated, UCH‐L1 expression was significantly increased. Furthermore, activation of NF‐κB signaling by the inflammatory stimulator lipopolysaccharide and TNFα resulted in a decrease of UCH‐L1 gene expression by inhibiting its transcription. As NF‐κB is an important signaling module in inflammatory response, our study suggests a possibility that inflammation might compromise neuronal functions via the interaction of NF‐κB and UCH‐L1. A better understanding of the NF‐κB‐regulated UCH‐L1 transcription will provide insights to the role of inflammatory responses in Alzheimer’s disease and Parkinson’s disease.