Lysosomal processing of progranulin

Zhou, Xiaolai; Paushter, Daniel H.; Feng, Tuancheng; Sun, Lirong; Reinheckel, Thomas; Hu, Fenghua

doi:10.1186/s13024-017-0205-9

Cited by 75 publications

(85 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionsupporting

confidence: 83%

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

Cortopassi²,

et al. 2018

Preprint

View full text Add to dashboard Cite

2The progressive failure of protein homeostasis is a hallmark of aging and a common feature in 3 neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal 4 proteases (or cathepsins) are key contributors to maintenance of protein homeostasis with age. 5 Here, we identify the cysteine-rich granulin peptides as a new class of regulators of lysosomal 6 aspartyl protease activity. Granulins are produced in an age and stress-dependent manner through 7 cleavage of the neurodegenerative disease protein, progranulin. Once liberated, granulins 8 selectively interact with the aspartyl protease ASP-3/cathepsin D to impair enzymatic activity. 9 Consequently, protein homeostasis and lysosome function is disrupted, prompting cells to 10 activate a compensatory transcriptional program. Our results support a model in which granulin 11 production modulates a critical transition between the normal, physiological regulation of 12 protease activity and the impairment of lysosomal function that can occur with age and disease. 13 14

show abstract

Section: Discussionsupporting

confidence: 83%

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

Cortopassi²,

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…Additionally, PGRN has been shown to be processed into individual granulin peptides within the lysosome (32,33) and two of these peptides, Grn E and Grn F, have been shown to interact with GBA (37,38). Since both PGRN and Grn peptides were pulled down in the anti-PGRN IP (Fig.…”

Section: Pgrn Interacts With Gbamentioning

confidence: 99%

“…In addition to the connection to NCL, increasing lines of evidence indicate that PGRN is likely to be involved in lysosomal physiology. In addition to being lysosomally localized, having two independent trafficking pathways to the lysosome (29,30), and being under transcriptional regulation with the majority of known lysosomal proteins (31), PGRN has recently been shown to be proteolytically processed to produce stable and functional granulin peptides in the lysosome (32)(33)(34), and is linked to the direct or indirect regulation of two lysosomal hydrolases, cathepsin D (CTSD) and glucocerebrosidase (GBA). PGRN was shown to stabilize and directly modulate the activity of cathepsin D in vitro and PGRN deficiency results in a reduction of cathepsin D activity in vivo (28,35,36).…”

Section: Introductionmentioning

confidence: 99%

Progranulin deficiency leads to reduced glucocerebrosidase activity

Zhou

Paushter

Pagan

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL). Although the exact function of PGRN is unknown, it has been increasingly implicated in lysosomal physiology. Here we report that PGRN interacts with the lysosomal enzyme, glucocerebrosidase (GBA), and is essential for proper GBA activity. GBA activity is significantly reduced in tissue lysates from PGRN-deficient mice. This is further evidence that reduced lysosomal hydrolase activity may be a pathological mechanism in cases of GRN-related FTLD and NCL.

show abstract

“…The presence of granulins only in the haploinsufficiency state could explain why TDP-43 pathology is not seen in the null state [18]. Several lysosomal proteases that cleave progranulin have recently been identified [32][33][34], although how those proteases decide when and where to cleave progranulin remains unknown. This study prompts several important follow up questions regarding the rate and order in which granulins are liberated from progranulin, how pH changes impact the predicted association of granulins with lysosomal proteases and whether increased granulin impact other neurodegenerative disorders such as Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

“…Granulins are highly conserved, disulfide-bonded miniproteins with unknown biological function [27][28][29][30][31]. Like progranulin, granulin peptides have been shown to localize to the endolysosomal compartment [32], and can be generated through the action of cysteine proteases on progranulin [32][33][34]. Owing to the twelve cysteines and six disulfide bonds found in each cleaved granulin, these peptides adopt a stacked β-sheet configuration that is compact, structurally stable and potentially protease resistant [35].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Lysosomal processing of progranulin

Cited by 75 publications

References 29 publications

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

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

Progranulin deficiency leads to reduced glucocerebrosidase activity

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

Contact Info

Product

Resources

About