Galectin-3 Coordinates a Cellular System for Lysosomal Repair and Removal

Jia, Jingyue; Claude-Taupin, Aurore; Gu, Yuexi; Choi, Su-Mi; Peters, Ryan; Bissa, Bhawana; Mudd, Michal H.; Allers, Lee; Pallikkuth, Sandeep; Lidke, Keith A.; Salemi, Michelle; Phinney, Brett S.; Mari, Muriel; Reggiori, Fulvio; Deretić, Vojo

doi:10.1016/j.devcel.2019.10.025

Cited by 234 publications

(320 citation statements)

References 123 publications

Supporting

Mentioning

273

Contrasting

Unclassified

Order By: Relevance

“…In this case, the assay can directly evaluate phagosomal leakage and becomes independent of lysosomal contribution. Another approach that is independent from phagosome maturation is the quantification of the recruitment of proteins that mark damaged membranes, such as galectins [167]. Galectins are cytosolic lectins that bind galactosides present on the luminal leaflet of organellar membranes and can therefore bind to phagosomal membranes when galactosides are exposed to the cytosol after membrane damage.…”

Section: Fluorescence-based Methodsmentioning

confidence: 99%

“…Galectins are cytosolic lectins that bind galactosides present on the luminal leaflet of organellar membranes and can therefore bind to phagosomal membranes when galactosides are exposed to the cytosol after membrane damage. Recruitment of galectins 3 and 8 to phagosomal membranes has been monitored by fluorescence microscopy [167][168][169]. Automated quantitative imaging of fluorescent puncta may be performed using highcontent analysis platforms [167].…”

Section: Fluorescence-based Methodsmentioning

confidence: 99%

See 1 more Smart Citation

A guide to measuring phagosomal dynamics

Levin‐Konigsberg

Mantegazza

2020

The FEBS Journal

View full text Add to dashboard Cite

Phagocytosis is an essential mechanism for immunity and homeostasis, performed by a subset of cells known as phagocytes. Upon target engulfment, de novo formation of specialized compartments termed phagosomes takes place. Phagosomes then undergo a series of fusion and fission events as they interact with the endolysosomal system and other organelles, in a dynamic process known as phagosome maturation. Because phagocytes play a key role in tissue patrolling and immune surveillance, phagosome maturation is associated with signaling pathways that link phagocytosis to antigen presentation and the development of adaptive immune responses. In addition, and depending on the nature of the cargo, phagosome integrity may be compromised, triggering additional cellular mechanisms including inflammation and autophagy. Upon completion of maturation, phagosomes enter a recently described phase: phagosome resolution, where catabolites from degraded cargo are metabolized, phagosomes are resorbed, and vesicles of phagosomal origin are recycled. Finally, phagocytes return to homeostasis and become ready for a new round of phagocytosis. Altogether, phagosome maturation and resolution encompass a series of dynamic events and organelle crosstalk that can be measured by biochemical, imaging, photoluminescence, cytometric, and immune-based assays that will be described in this guide.

show abstract

Section: Fluorescence-based Methodsmentioning

confidence: 99%

Section: Fluorescence-based Methodsmentioning

confidence: 99%

A guide to measuring phagosomal dynamics

Levin‐Konigsberg

Mantegazza

2020

The FEBS Journal

View full text Add to dashboard Cite

show abstract

“…Recently, it has emerged that the lysosomal limiting membrane is susceptible to damage resulting from undigested/undigestible substrates that accumulate within the lumen (Jia et al, 2020;Maejima et al, 2013; upon loss of NPC1 function might compromise the integrity of the lysosomal membrane. An early detection system provided by the Endosomal Sorting Complex Required for Transport (ESCRT) III proteins detects 'microtears' in the lysosomal membrane and repairs them via a membrane scission process that is thought to topologically resemble ESCRT III-mediated intraluminal vesicle budding during endosomal maturation (Nguyen et al, 2020;Radulovic et al, 2018;Schöneberg et al, 2017;Skowyra et al, 2018).…”

Section: Npc1-null Lysosomes Display Increased Susceptibility To Membmentioning

confidence: 99%

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

Davis

Shin

Lim

et al. 2020

Preprint

View full text Add to dashboard Cite

Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function and neurodegeneration. The compositional and functional alterations in NPC lysosomes, and how aberrant cholesterol-mTORC1 signaling contributes to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion and enhanced membrane damage. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.

show abstract

“…Galectin-3 can coordinate repair, removal, and replacement of lysosomes (Jia et al 2020), and its upregulation may reflect attempts by senescent cells to repair deteriorating lysosomes (Park et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

Delfarah

Zheng

et al. 2020

Preprint

View full text Add to dashboard Cite

Cellular senescence is the natural program by which cells enter a permanent cell cycle arrest in response to stresses including replicative exhaustion, oncogenic signaling, or DNA damage. Although senescence exerts beneficial effects by acting as a barrier against tumorigenesis, senescent cells can also drive chronic inflammation and age-related diseases through secretion of cytokines and other inflammatory proteins. Therefore, the identification of senolytic compounds that specifically eliminate senescent cells has become an area of great therapeutic promise. Here, we used mass spectrometry-based proteomics to identify senescence biomarkers in primary human mammary epithelial cells (HMECs), a model system for aging. By integrating proteomic data from replicative senescence, immortalization by telomerase reactivation, and drug-induced senescence, we identified a robust HMEC proteomic signature of senescence consisting of 57 upregulated and 29 downregulated proteins. This senescence signature identified both well-known senescence biomarkers, including downregulation of the nuclear lamina protein lamin-B1 (LMNB1), as well as novel biomarkers such as upregulation of the β-galactoside-binding protein galectin-7 (LGALS7). Then, we integrated our proteomic signature of senescence with large-scale drug screening databases to predict that EGFR inhibitors, MEK inhibitors, and dasatinib are novel senolytics in HMEC. Taken together, our results support that the combination of quantitative proteomics and public drug screening databases is a powerful approach to identify senescence biomarkers and novel senolytic compounds.

show abstract

Galectin-3 Coordinates a Cellular System for Lysosomal Repair and Removal

Cited by 234 publications

References 123 publications

A guide to measuring phagosomal dynamics

A guide to measuring phagosomal dynamics

NPC1-mTORC1 signaling Couples Cholesterol Sensing to Organelle Homeostasis and is a Targetable Pathway in Niemann-Pick type C

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

Contact Info

Product

Resources

About