Beyond indigestion: emerging roles for lysosome-based signaling in human disease

Ferguson, Shawn M.

doi:10.1016/j.ceb.2015.04.014

Cited by 62 publications

(56 citation statements)

References 95 publications

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“…Interestingly, a subset of HPS patients develop Crohn’s disease-like colitis, suggesting that genetic alterations to lysosomal function can result in Crohn’s-like pathologies (Hazzan et al, 2006). Although inherited lysosomal disorders are known to cause severe disease, our data suggest that subtle changes to lysosomal function through genetic polymorphisms can alter susceptibility to microbes, particularly in the gut at the host-commensal interface (Ferguson, 2015). …”

Section: Discussionmentioning

confidence: 98%

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Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

et al. 2016

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SUMMARY Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense.

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Section: Discussionmentioning

confidence: 98%

“…Recent studies have shed light on the critical role that lysosomes play in the immune response, signaling, tissue repair, and cellular energetics, and it is likely that disruptions in these responses contribute to IBD susceptibility (Ferguson, 2015; Settembre et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

et al. 2016

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“…However, new findings indicate that lysosomes also play critical roles in supporting cell metabolism, membrane homeostasis, cholesterol signaling, and antigen processing and presentation (Appelqvist et al, 2013; Ferguson, 2015). We found greater than 2-fold variation in BG microglial lysosome content, supporting the conclusion that microglial functional status varies across BG nuclei.…”

Section: Discussionmentioning

confidence: 99%

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Biase

Schuebel

Fusfeld

et al. 2017

Neuron

339

348

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SUMMARY Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei. Region-specific phenotypes of BG microglia emerged during the second postnatal week and were re-established following genetic or pharmacological microglial ablation and repopulation in the adult, indicating that local cues play an ongoing role in shaping microglial diversity. These findings demonstrate that microglia in the healthy brain exhibit a spectrum of distinct functional states and provide a critical foundation for defining microglial contributions to BG circuit function.

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“…This is currently being explored in clinical trials by interfering with lysosome function (White et al, 2015). Targeting the MiTF/TFE family of transcription factors and master regulators of autophagy and lysosomal biogenesis activated in many cancers (Ferguson, 2015) may provide another option and may identify tumors potentially sensitive to autophagy inhibition.…”

Section: Targeting Of Mitochondrial Metabolism For Cancer Therapymentioning

confidence: 99%

Mitochondria and Cancer

2016

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Decades ago Otto Warburg observed that cancers ferment glucose in the presence of oxygen, suggesting that defects in mitochondrial respiration may be the underlying cause of cancer. We now know that the genetic events, which drive aberrant cancer cell proliferation, also alter biochemical metabolism including promoting aerobic glycolysis, but do not typically impair mitochondrial function. Mitochondria supply energy, provide building blocks for new cells, and control redox homeostasis, oncogenic signaling, innate immunity and apoptosis. Indeed, mitochondrial biogenesis and quality control are often upregulated in cancers. While some cancers have mutations in nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle enzymes that produce oncogenic metabolites, there is negative selection for pathogenic mitochondrial genome mutations. Eliminating mitochondrial DNA limits tumorigenesis and rare human tumors with mutant mitochondrial genomes are relatively benign. Thus, mitochondria play a central and multi-functional role in malignant tumor progression, and targeting mitochondria provides therapeutic opportunities.

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Beyond indigestion: emerging roles for lysosome-based signaling in human disease

Cited by 62 publications

References 95 publications

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

Mitochondria and Cancer

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