The lysosomal protein cathepsin L is a progranulin protease

Abstract

Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments. Further, PGRN and Cat L co-localize in lysosomes of HEK293 cells, iPSC-derived neurons and human cortical neurons from human postmortem tissue. These data identify Cat L as a key intracellular lysosomal PGRN protease, and provides an intriguing new link between lysosomal dysfunction and FTLD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0196-6) contains supplementary material, which is available to authorized users.

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

“…The presence of granulins only in the happloinsufficient state could explain why TDP-43 pathology is not seen in the null state (Smith et al, 2012). Several lysosomal proteases that cleave progranulin have recently been identified (Holler et al, 2017, Lee et al, 2017, Zhou et al, 2017b), which helps to validate our findings. This study now prompts several important follow up questions determining the rate and order in which granulins are liberated from progranulin, exploring how pH changes impact the predicted association of granulins with aspartyl proteases and asking if granulins act more generally in other neurodegenerative disorders such as Alzheimer’s disease.…”

An Autophagy Modifier Screen Identifies Small Molecules Capable of Reducing Autophagosome Accumulation in a Model of CLN3-Mediated Neurodegeneration

“…Six protease inhibitors and three topoisomerase inhibitors were also among the compounds identified as phenotype enhancers, with the latter group also showing substantial toxicity. Among the protease inhibitors, which were only marginally toxic or showed no toxicity, it was notable that three of the compounds were cathepsin B and/or L inhibitors, both enzymes that have been linked to NCL-related pathways [27][28][29]. Finally, consistent with our previous study, several calcium channel blockers were among the phenotype enhancers, including two that target endoplasmic reticulum (ER) calcium channels, like thapsigargin (Table S3, [13]).…”

Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis

“…Based on recent reports of efficient progranulin processing into granulin peptides within lysosomes (Holler et al, 2017), the increased abundance of full length progranulin is consistent with a defect in its lysosome delivery. Impaired function of cathepsin L, a major protease that mediates conversion of progranulin into granulins (Holler et al, 2017;Lee et al, 2017), could also contribute to this phenotype. In parallel with defects in lysosome localization and processing, we also observed greater secretion of the unprocessed forms of lysosomal proteins including: progranulin and cathepsins B, D and L (Supplemental Fig.…”