Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response

Abstract

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 are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age-and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. 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.

Caenorhabditis elegans as a Useful Model for Studying Aging Mutations

“…Different upstream signals stimulate partially overlapping sets of downstream mediators and processes that ultimately extended the lifespan. Meanwhile, epigenetic regulation in cooperation with transcriptional regulators influence the functions of cells and the fate of organisms, and could act as markers of aging ( 51 ). Epigenetic regulation involves DNA methylation, chromatin remodeling, post-translational modifications (PTMs) of histones, and non-coding RNA transcription ( 28 ).…”

Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration

“…This study sought to better understand all aspects of PGRN cleavage into granulins, from the proteases involved and pH-dependence of cleavage to the MGFs/granulins produced and relevance to human disease. The normal functions of PGRN as an activator of CTSD are slowly being elucidated [14,46]. However, granulins are less well-understood.…”

“…Granulins F levels are increased in the degenerating regions of the brains from FTLD-TDP-Pgrn patients PGRN haploinsu ciency predisposes to FTLD-TDP. Interestingly, in C. elegans, the processing of progranulin to granulins increases with age [46]. Further, the presence of an MGF containing granulin E is decreased in FTLD-TDP [12].…”

MiT/TFE Family of Transcription Factors: An Evolutionary Perspective

“…Moreover, HLH-30 is activated in response to age- and stress-related accumulation of granulins in the endo-lysosomal compartment, leading to the impairment of lysosomal function ( Butler et al, 2019 ). Also, in both C. elegans and mammalian cell models of aggregation-prone proteins, HLH-30 and TFEB activation are regulated by reduced glutathione and the activity of glutathione reductase (GSR-1) ( Guerrero-Gomez et al, 2019 ).…”