UCH-L1 C-terminus plays a key role in protein stability but its farnesylation is not required for membrane association in primary neurons [Cell Biology]

October 17th, 2014 by Bishop, P., Rubin, P., Thomson, A. R., Rocca, D., Henley, J. M.

Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) is a deubiquitinating enzyme (DUB) that is highly expressed in neurons. A possible role for UCH-L1 in neurodegeneration has been highlighted because of its presence in Lewy Bodies associated with Parkinsons disease and neurofibrillary tangles observed in Alzheimers disease. UCH-L1 exists in two forms in neurons, a soluble cytoplasmic form (UCH-L1C) and a membrane-associated form (UCH-L1M). Alzheimers brains show reduced levels of soluble UCH-L1C correlating with the formation of UCH-L1-immunoreactive tau tangles, whereas UCH-L1M has been implicated in α-synuclein dysfunction. Given these reports of divergent roles, we investigated the properties of UCH-L1 membrane-association. Surprisingly, our results indicate that UCH-L1 does not partition to the membrane in the cultured cell lines we tested. Furthermore, in primary cultured neurons, a proportion of UCH-L1M does partition to the membrane, but, contrary to a previous report, this does not require farnesylation. Deletion of the four C-terminal residues caused the loss of protein solubility, abrogation of substrate binding, increased cell death and an abnormal intracellular distribution, consistent with protein dysfunction and aggregation. These data indicate that UCH-L1 is differently processed in neurons compared to clonal cell lines and that farnesylation does not account for the membrane association in neurons.
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