Abstract 1998 Proteasomal activity in C. elegans is regulated by temperature

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A decline of cellular protein homeostasis (proteostasis) can result in the accumulation of damaged and aggregation-prone proteins which can underly age-related diseases. Proteasome-mediated degradation of damaged or superfluous proteins is one major cellular mechanism to maintain proteostasis. While reduced proteasomal activity can lead to age-related diseases, the enhancement of proteasomal activity can reduce disease-related protein aggregation and promote longevity. Previous work in some animal models inversely correlates proteasomal activity with temperature; however, the impact of long-term temperature exposure on proteasomal activity has not been fully described at the organismal level in in C. elegans with either wild type or hyperactive proteasomal activity. We hypothesize that culturing animals at the low and high laboratory temperature range (15˚C and 25˚C) causes temperature-dependent impacts on global proteostasis in C. elegans. Using animal lysate and fluorogenic substrates, we assessed proteasomal cleavage after basic (trypsin-like, TL), acidic (chymotrypsin-like, CT-L) and hydrophobic (caspase-like, CL) residues. We find that lysate from animals cultured at 15˚C have robust TL and CL activity; whereas, animals cultured at 25˚C have robust CT-L activity. The observed CT-L degradation at 25 ˚C can be completely inhibited using proteasomal inhibitors such as bortezomib and MG132. In contrast, animals cultured at low temperature (15˚C) show continued and substantial CT-L cleavage in the presence of proteasomal inhibitors. We observe that residual CT-L activity in 15˚C lysate in the presence of proteasome inhibitor could be completely abolished by including a protease inhibitor cocktail (PIC), suggesting the contribution of proteases to CT-L proteolysis. However, testing the components of PIC, individually or combinatorially, did not result in pronounced inhibition, suggesting a potential global upregulation of protease activity in animals cultured at low temperatures. Identification of temperature-dependent impacts on protease activity emphasizes the role of non-proteasomal degradation in maintaining proteostasis networks and highlights the importance of considering culture temperature in whole animal studies of proteostasis. This work is supported by the Wabash College Haines Biochemistry Fund, the Wabash College Treves Biology Fund, and NSF Grant MCB-2146714.

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