Increased activity of proteasome associated deubiquitinating enzyme, USP14, accompanies lowered proteasomal proteolysis in primary human T lymphocytes during aging. (63.18)

Abstract Aging is accompanied by a significant decline in proteasomal proteolysis that underlies lowered induction of T cell functional response. As USP14, found in association with the proteasome is both necessary and important in mediating ubiquitin trimming from proteasomal substrates, we evaluated functional USP14 levels by employing active site probes for proteasome associated deubiquitinating enzymes (DUBS). Our studies for the first time demonstrate that in T lymphocytes obtained from elderly donors, USP14 activity is significantly higher than those from young donors, and additionally, increased functional activity of USP14 accompanies conditions under which 26S proteasome catalytic activities are inhibited. UCH37, another DUBS associated with 26S proteasome appears to demonstrate only a modest increase in activity. Alteration in USP14 activity appears to be reciprocally regulated by the catalytic function of the 26S proteasome. Increase in USP14 activity is accompanied by an overall increase in USP14 protein but not mRNA expression in cells from the elderly. Thus, DUB activity associated with the proteasome demonstrates compensatory increase in activity during aging, and may regulate local levels of monomeric ubiquitin.