Biology subjects

Butler, V. J.

Publications and source records attributed to Butler, V. J..

2 recordsLinked to original sources

bioRxiv2019

Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy

Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear. Here, we report that NDGA is an inhibitor of the epigenetic regulator p300. We find that NDGA inhibits p300 acetyltransferase activity in vitro and suppresses acetylation of a key p300 target in histones (i.e., H3K27) in cells. We use the cellular thermal shift assay to uniquely demonstrate NDGA binding to p300 in cells. Finally, in agreement with recent findings indicating that p300 is a potent blocker of autophagy, we show that NDGA treatment induces autophagy. These findings identify p300 as a novel target of NDGA and provide mechanistic insight into its role in longevity.

cell biology↗

bioRxiv2018

C. elegans granulins promote an age-associated decline in protein homeostasis via lysosomal protease inhibition

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases (or cathepsins) are key contributors to maintenance of protein homeostasis with age. Here, we identify the cysteine-rich granulin peptides as a new class of regulators of lysosomal aspartyl protease activity. Granulins are produced in an age and stress-dependent manner through cleavage of the neurodegenerative disease protein, progranulin. Once liberated, granulins selectively interact with the aspartyl protease ASP-3/cathepsin D to impair enzymatic activity. Consequently, protein homeostasis and lysosome function is disrupted, prompting cells to activate a compensatory transcriptional program. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

neuroscience↗