Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

Weiss-Sadan, Tommy; Itzhak, Gal; Kaschani, Farnusch; Yu, Zhanru; Mahameed, Mohamed; Anaki, Adi; Ben-Nun, Yael; Merquiol, Emmanuelle; Tirosh, Boaz; Kessler, Benedikt M.; Kaiser, Markus; Blum, Galia

doi:10.1074/mcp.ra119.001392

Cited by 7 publications

(4 citation statements)

References 62 publications

(75 reference statements)

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“…It may be speculated that this is at least partly due to enhanced glycolytic activity. In line with these data, a recently published study in murine embryonic fibroblasts also revealed that cathepsin L inhibition led to a shift in cellular energy production towards glycolysis [79].…”

Section: Discussionsupporting

confidence: 66%

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oelschlaegel

Sadan

Salpeter

et al. 2020

Cancers

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Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

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Section: Discussionsupporting

confidence: 66%

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oelschlaegel

Sadan

Salpeter

et al. 2020

Cancers

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“…It is unclear, however, whether the repertoire of substrates is the same for single-chain and two-chain cathepsin L. Shifting the balance from the two-chain to single-chain form upon legumain inhibition could possibly account for some of the changes that we observed in both our preTAILS and TAILS analyses. Recent work by Weiss-Sadan has demonstrated a role for cathepsin L in the regulation of metabolism and mitochondrial dynamics. , In our preTAILS analysis, we identified a number of mitochondrial proteins associated with a metabolic activity that were differentially regulated upon legumain inhibition. These observations could be at least partially explained by the effects of legumain on cathepsin L. The prevalence of P1 arginine residues among the cleavage events identified in both DMSO- and LI-1-treated cells may be driven by the activity of cathepsin L or other cysteine cathepsins.…”

Section: Discussionmentioning

confidence: 94%

“…Recent work by Weiss-Sadan has demonstrated a role for cathepsin L in the regulation of metabolism and mitochondrial dynamics. 48,49 In our preTAILS analysis, we identified a number of mitochondrial proteins associated with a metabolic activity that were differentially regulated upon legumain inhibition. These observations could be at least partially explained by the effects of legumain on cathepsin L. The prevalence of P1 arginine residues among the cleavage events identified in both DMSO-and LI-1-treated cells may be driven by the activity of cathepsin L or other cysteine cathepsins.…”

Section: ■ Discussionmentioning

confidence: 99%

N-Terminomics/TAILS Profiling of Macrophages after Chemical Inhibition of Legumain

et al. 2019

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Legumain (asparaginyl endopeptidase) is the only protease with a preference for cleavage after asparagine residues. Increased legumain activity is a hallmark of inflammation, neurodegenerative diseases, and cancer, and legumain inhibitors have exhibited therapeutic effects in mouse models of these pathologies. Improved knowledge of its substrates and cellular functions is a requisite to further validation of legumain as a drug target. We, therefore, aimed to investigate the effects of legumain inhibition in macrophages using an unbiased and systematic approach. By shotgun proteomics, we identified 16 094 unique peptides in RAW264.7 cells. Among these, 326 unique peptides were upregulated in response to legumain inhibition, while 241 were downregulated. Many of these proteins were associated with mitochondria and metabolism, especially iron metabolism, indicating that legumain may have a previously unknown impact on related processes. Furthermore, we used N-terminomics/ TAILS (terminal amine isotopic labeling of substrates) to identify potential substrates of legumain. We identified three new proteins that are cleaved after asparagine residues, which may reflect legumain-dependent cleavage. We confirmed that frataxin, a mitochondrial protein associated with the formation of iron−sulfur clusters, can be cleaved by legumain. This further asserts a potential contribution of legumain to mitochondrial function and iron metabolism. Lastly, we also identified a potential new cleavage site within legumain itself that may give rise to a 25 kDa form of legumain that has previously been observed in multiple cell and tissue types. Collectively, these data shed new light on the potential functions of legumain and will be critical for understanding its contribution to disease.

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“…Cathepsin B (CATB), a lysosomal protease, is overexpressed in human breast cancers with high metabolic activity and is correlated with poor prognosis. Cathepsin B is a also regulator of metabolic processes [125]. It has been shown that HIF1A is involved in the modulated glycolytic activity.…”

Section: Poly I:cmentioning

confidence: 99%

Immunostimulant Bathing Influences the Expression of Immune- and Metabolic-Related Genes in Atlantic Salmon Alevins

Figueiredo

Kristoffersen

Bhat

et al. 2021

Biology

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Disease resistance of fish larvae may be improved by bath treatment in water containing immunostimulants. Pattern recognition receptors, such as TLR3, TLR7, and MDA5, work as an “early warning” to induce intracellular signaling and facilitate an antiviral response. A single bath of newly hatched larvae, with Astragalus, upregulated the expression of IFNα, IFNc, ISG15, MDA5, PKR, STAT1, TLR3, and TLR7 immune genes, on day 4 post treatment. Similar patterns were observed for Hyaluronic acid and Poly I:C. Increased expression was observed for ISG15, MDA5, MX, STAT1, TLR3, TLR7, and RSAD2, on day 9 for Imiquimod. Metabolic gene expression was stimulated on day 1 after immunostimulant bath in ULK1, MYC, SLC2A1, HIF1A, MTOR, and SIX1, in Astragalus, Hyaluronic acid, and Imiquimod. Expression of NOS2 in Poly I:C was an average fourfold above that of control at the same timepoint. Throughout the remaining sampling days (2, 4, 9, 16, 32, and 45 days post immunostimulant bath), NOS2 and IL1B were consistently overexpressed. In conclusion, the immunostimulants induced antiviral gene responses, indicating that a single bath at an early life stage could enable a more robust antiviral defense in fish. Additionally, it was demonstrated, based on gene expression data, that cell metabolism was perturbed, where several metabolic genes were co-regulated with innate antiviral genes.

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Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation

Cited by 7 publications

References 62 publications

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

N-Terminomics/TAILS Profiling of Macrophages after Chemical Inhibition of Legumain

Immunostimulant Bathing Influences the Expression of Immune- and Metabolic-Related Genes in Atlantic Salmon Alevins

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