Lysosomal solute carrier transporters gain momentum in research

Bissa, Bhawana; Beedle, Aaron M.; Govindarajan, Rajgopal

doi:10.1002/cpt.450

Cited by 43 publications

(32 citation statements)

References 5 publications

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“…After protein digestion has been completed, transporter proteins in the lysosomal membrane release (primarily) individual amino acids back into the cytosol for new protein synthesis or energy production. 5 Lysosomes are crucial for maintaining cellular homeostasis, but they are also uniquely susceptible to problems when substrates cannot be hydrolyzed. For example, genetic modifications reducing the efficacy of a lysosomal hydrolase are the most common cause of lysosomal storage disorders.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Isomerization of Long-Lived Proteins Provides a Molecular Mechanism for the Lysosomal Failure Observed in Alzheimer’s Disease

et al. 2019

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Proteinaceous aggregation is a well-known observable in Alzheimer’s disease (AD), but failure and storage of lysosomal bodies within neurons is equally ubiquitous and actually precedes bulk accumulation of extracellular amyloid plaque. In fact, AD shares many similarities with certain lysosomal storage disorders though establishing a biochemical connection has proven difficult. Herein, we demonstrate that isomerization and epimerization, which are spontaneous chemical modifications that occur in long-lived proteins, prevent digestion by the proteases in the lysosome (namely, the cathepsins). For example, isomerization of aspartic acid into l -isoAsp prevents digestion of the N-terminal portion of Aβ by cathepsin L, one of the most aggressive lysosomal proteases. Similar results were obtained after examination of various target peptides with a full series of cathepsins, including endo-, amino-, and carboxy-peptidases. In all cases peptide fragments too long for transporter recognition or release from the lysosome persisted after treatment, providing a mechanism for eventual lysosomal storage and bridging the gap between AD and lysosomal storage disorders. Additional experiments with microglial cells confirmed that isomerization disrupts proteolysis in active lysosomes. These results are easily rationalized in terms of protease active sites, which are engineered to precisely orient the peptide backbone and cannot accommodate the backbone shift caused by isoaspartic acid or side chain dislocation resulting from epimerization. Although Aβ is known to be isomerized and epimerized in plaques present in AD brains, we further establish that the rates of modification for aspartic acid in positions 1 and 7 are fast and could accrue prior to plaque formation. Spontaneous chemistry can therefore provide modified substrates capable of inducing gradual lysosomal failure, which may play an important role in the cascade of events leading to the disrupted proteostasis, amyloid formation, and tauopathies associated with AD.

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Section: Introductionmentioning

confidence: 99%

Spontaneous Isomerization of Long-Lived Proteins Provides a Molecular Mechanism for the Lysosomal Failure Observed in Alzheimer’s Disease

et al. 2019

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“…It is widely expressed in human organs, tissues and cells, especially in the brain, adrenal glands and thyroid (10). Its main function is to participate in vesicle uptake, storage and secretion of adenosine triphosphate (ATP) as well as other nucleotides, and especially plays an important role in the ATP transport of airway epithelium and neutrophils, astrocytes, adrenal chromaffin cells and pancreatic cells (11). SLC17A9 can mediate ATP accumulation in lysosomes and is an indispensable factor for maintaining lysosomal physiology and cell viability (12).…”

Section: Introductionmentioning

confidence: 99%

Expression of SLC17A9 in hepatocellular carcinoma and its clinical significance

2020

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The present study aimed to investigate the expression and clinical significance of solute carrier family 17 member 9 (SLC17A9) in cancer tissues of patients with hepatocellular carcinoma (HCC). Ninety-eight patients with HCC were admitted to our hospital from January 2010 to December 2014. Their clinical data was retrospectively analyzed. The expression of SLC17A9 in HCC cancer tissues was detected by immunohistochemistry. Kaplan-Meier curve, log-rank test and Cox proportional hazard model analysis were used to analyze the tumor-free survival rate and overall survival rate. SLC17A9 expression was associated with Edmondson grade (P=0.04) and distant metastasis (P=0.03). The tumor-free survival (P=0.03) and overall survival (P= 0.01) of SLC17A9-high expression patients were significantly lower than those in SLC17A9-low expression patients. Multivariate analysis revealed that SLC17A9 expression (HR, 0.77; 95% CI, 0.27-2.47, P= 0.02) was an independent risk factor for tumor-free survival in patients with HCC, and the expression of SLC17A9 (HR, 1.81; 95% CI, 0.99-3.77, P=0.04) was an independent risk factor for overall survival in patients with HCC. In conclusion, SLC17A9 can be used as a new molecular marker to predict the poor prognosis of patients with HCC.

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“…Like L. pneumophila, intravacuolar Chlamydia trachomatis and Salmonella enterica use SLC transporters to derive critical nutrients, including glucose (SLC35D2) and arginine (SLC7A1), respectively (6)(7)(8). Lysosomes contain several SLC transporters, including those that pump amino acids (SLC7A14 and SLC36A1) and glucose (SLC2A8) into the vesicle lumen (41). Given the lysosomal character of the CCV, the vacuole likely contains these and other transport systems that provide C. burnetii with basic nutrients.…”

Section: Discussionmentioning

confidence: 99%

Replication of Coxiella burnetii in a Lysosome-Like Vacuole Does Not Require Lysosomal Hydrolases

2019

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Coxiella burnetii is an intracellular bacterium that causes query, or Q fever, a disease that typically manifests as a severe flu-like illness. The initial target of C. burnetii is the alveolar macrophage. Here, it regulates vesicle trafficking pathways and fusion events to establish a large replication vacuole called the Coxiella-containing vacuole (CCV). Similar to a phagolysosome, the CCV has an acidic pH and contains lysosomal hydrolases obtained via fusion with late endocytic vesicles. Lysosomal hydrolases break down various lipids, carbohydrates, and proteins; thus, it is assumed C. burnetii derives nutrients for growth from these degradation products. To investigate this possibility, we utilized a GNPTAB−/− HeLa cell line that lacks lysosomal hydrolases in endocytic compartments. Unexpectedly, examination of C. burnetii growth in GNPTAB−/− HeLa cells revealed replication and viability are not impaired, indicating C. burnetii does not require by-products of hydrolase degradation to survive and grow in the CCV. However, although bacterial growth was normal, CCVs were abnormal, appearing dark and condensed rather than clear and spacious. Lack of degradation within CCVs allowed waste products to accumulate, including intraluminal vesicles, autophagy protein LC3, and cholesterol. The build-up of waste products coincided with an altered CCV membrane, where LAMP1 was decreased and CD63 and LAMP1 redistributed from a punctate to uniform localization. This disruption of CCV membrane organization may account for the decreased CCV size due to impaired fusion with late endocytic vesicles. Collectively, these results demonstrate lysosomal hydrolases are not required for C. burnetii survival and growth but are needed for normal CCV development. These data provide insight into mechanisms of CCV biogenesis while raising the important question of how C. burnetii obtains essential nutrients from its host.

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Lysosomal solute carrier transporters gain momentum in research

Cited by 43 publications

References 5 publications

Spontaneous Isomerization of Long-Lived Proteins Provides a Molecular Mechanism for the Lysosomal Failure Observed in Alzheimer’s Disease

Spontaneous Isomerization of Long-Lived Proteins Provides a Molecular Mechanism for the Lysosomal Failure Observed in Alzheimer’s Disease

Expression of SLC17A9 in hepatocellular carcinoma and its clinical significance

Replication of Coxiella burnetii in a Lysosome-Like Vacuole Does Not Require Lysosomal Hydrolases

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