Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide

Li, Baihui; Wang, Fengjuan; Schall, Nicolas; Muller, Sylviane

doi:10.1016/j.jaut.2018.02.005

Cited by 41 publications

(53 citation statements)

References 59 publications

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“…Recent studies have demonstrated an increase in the level of macroautophagy in salivary gland T lymphocytes and in tears and conjunctival epithelial cells of patients with primary Sjögren's syndrome (SjS) 107,108 . Alteration of CMA activity was also recently found to occur in the salivary glands of MRL/lpr mice that develop a second ary SjS like disease 56 . Lysosomes, which as discussed are mechanistically involved at the downstream level of both macroautophagy and CMA, were found to be altered in salivary glands.…”

Section: Sjögren's Syndromementioning

confidence: 74%

“…Lysosomes, which as discussed are mechanistically involved at the downstream level of both macroautophagy and CMA, were found to be altered in salivary glands. Flow cytometry analyses revealed that the mean pH of acidic vesicles in MRL/ lpr salivary glands was significantly higher compared with those in mouse control glands and the ATP con tent was significantly diminished in MRL/lpr salivary gland cells 56 . Furthermore, amounts of several leukocyte glycosidases and proteases were revealed to be increased in leukocytes of patients with SjS in comparison with healthy controls 55 .…”

Section: Sjögren's Syndromementioning

confidence: 83%

“…Defects in Niemann-Pick C1 and C2 proteins lead to accumulation of cholesterol and glycosphingolipids in lysosomes and cause hepatic, pulmonary and neuropsychiatric disorders in humans 45 Defective autophagy processes observed in SGs of MRL/lpr mice 56 Crohn's disease Abnormal lysosomal pH Deregulation of proton-sensing G protein-coupled receptor (GPR65) was observed in both mice and human 57 www.nature.com/nrd peptide epitopes for further processing, clear possibly deleterious apoptotic debris, fuel the amino acid pool and produce energy ( Fig. 1).…”

Section: Npc1 Membrane Protein Involved In Lipid Transportmentioning

confidence: 99%

“…In line with these internal alterations of lysosomes, notably those related to cathepsin functioning, deregu lation of autophagy has been reported to contribute to lupus pathology 92,97-100 . Autophagy failures have been described in the lymphocytes of MRL/lpr mice and (NZBxNZW)F1 mice 56,92,97,101 (two spontaneous murine models of systemic autoimmunity of distinct genetic ori gins and that display different MHC haplotypes) as well as in T and B lymphocytes of patients with SLE 97,98,100 . Murine and human T cells from the peripheral blood showed a significant accumulation of autophagic vac uoles compared with normal 97 .…”

Section: Selective Loss Of Gcase In Lysosomes Relates To the Decreasementioning

confidence: 99%

“…For example, azithromycin, an antibiotic with anti inflammatory properties that is used in the treatment of patients with chronic inflammatory lung diseases such as cystic fibrosis, was found to block autophagy in macrophages, inhibiting intracellular kill ing of mycobacteria within them and, thereby, increasing the risk of mycobacterial infection 204 . Second, in some diseases, autophagy may be enhanced in certain tissues or organs but compromised in others, for example in the spleen and salivary glands of MRL/lpr mice 56 . This phe nomenon makes it highly challenging to identify a single drug able to correct a failure, unless a cell specific target ing molecule could be incorporated into the autophagy activator/inhibitor to enable tissue specificity 205 .…”

Section: Wwwnaturecom/nrdmentioning

confidence: 99%

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Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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Section: Sjögren's Syndromementioning

confidence: 74%

Section: Sjögren's Syndromementioning

confidence: 83%

Section: Npc1 Membrane Protein Involved In Lipid Transportmentioning

confidence: 99%

Section: Selective Loss Of Gcase In Lysosomes Relates To the Decreasementioning

confidence: 99%

Section: Wwwnaturecom/nrdmentioning

confidence: 99%

See 3 more Smart Citations

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

Self Cite

516

374

View full text Add to dashboard Cite

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Modes and Mechanisms of Salivary Gland Epithelial Cell Death in Sjogren's Syndrome

et al. 2023

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Sjogren's syndrome is an autoimmune disease in middle and old‐aged women with a dry mucosal surface, which is caused by the dysfunction of secretory glands, such as the oral cavity, eyeballs, and pharynx. Pathologically, Sjogren's syndrome are characterized by lymphocyte infiltration into the exocrine glands and epithelial cell destruction caused by autoantibodies Ro/SSA and La/SSB. At present, the exact pathogenesis of Sjogren's syndrome is unclear. Evidence suggests epithelial cell death and the subsequent dysfunction of salivary glands as the main causes of xerostomia. This review summarizes the modes of salivary gland epithelial cell death and their role in Sjogren's syndrome progression. The molecular mechanisms involved in salivary gland epithelial cell death during Sjogren's syndrome as potential leads to treating the disease are also discussed.

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Lysosome‐Associated Membrane Protein 3 Induces Lysosome‐Dependent Cell Death by Impairing Autophagic Caspase 8 Degradation in the Salivary Glands of Individuals With Sjögren's Disease

Nakamura

Tanaka

Zheng

et al. 2023

Arthritis & Rheumatology

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ObjectiveLysosome‐associated membrane protein 3 (LAMP3) overexpression is implicated in the development and progression of Sjögren's disease (SjD) by inducing lysosomal membrane permeabilization (LMP) and apoptotic cell death in salivary gland epithelium. The aim of this study was to clarify the molecular details of LAMP3‐induced lysosome‐dependent cell death and to test lysosomal biogenesis as a therapeutic intervention.MethodsHuman labial minor salivary gland biopsies were analyzed using immunofluorescence staining for LAMP3 expression levels and galectin‐3 puncta formation, a marker of LMP. Expression level of caspase 8, an initiator of LMP, was determined by Western blotting in cell culture. Galectin‐3 puncta formation and apoptosis were evaluated in cell cultures and a mouse model treated with glucagon‐like peptide 1 receptor (GLP‐1R) agonists, a known promoter of lysosomal biogenesis.ResultsGalectin‐3 puncta formation was more frequent in the salivary glands of SjD patients compared to control glands. The proportion of galectin‐3 puncta–positive cells was positively correlated with LAMP3 expression levels in the glands. LAMP3 overexpression increased caspase 8 expression, and knockdown of caspase 8 decreased galectin‐3 puncta formation and apoptosis in LAMP3‐overexpressing cells. Inhibition of autophagy increased caspase 8 expression, while restoration of lysosomal function using GLP‐1R agonists decreased caspase 8 expression, which reduced galectin‐3 puncta formation and apoptosis in both LAMP3‐overexpressing cells and mice.ConclusionLAMP3 overexpression induced lysosomal dysfunction, resulting in lysosome‐dependent cell death via impaired autophagic caspase 8 degradation, and restoring lysosomal function using GLP‐1R agonists could prevent this. These findings suggested that LAMP3‐induced lysosomal dysfunction is central to disease development and is a target for therapeutic intervention in SjD.image

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Rescue of autophagy and lysosome defects in salivary glands of MRL/lpr mice by a therapeutic phosphopeptide

Cited by 41 publications

References 59 publications

Lysosomes as a therapeutic target

Lysosomes as a therapeutic target

Modes and Mechanisms of Salivary Gland Epithelial Cell Death in Sjogren's Syndrome

Lysosome‐Associated Membrane Protein 3 Induces Lysosome‐Dependent Cell Death by Impairing Autophagic Caspase 8 Degradation in the Salivary Glands of Individuals With Sjögren's Disease

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