Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux

Liu, Bin; Chen, Ran; Zhang, Yidan; Huang, Jinrong; Luo, Yonglun; Rosthøj, Susanne; Zhao, Chenyang; Jäättelä, Marja

doi:10.1016/j.celrep.2023.112137

Cited by 9 publications

(7 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is clearly demonstrated by the substantial sensitization to and inhibition of CAD-induced lysosome-dependent cancer cell death upon TMEM165 depletion and overexpression, respectively. These data emphasize the role of P2RX4-mediated lysosomal Ca 2+ release in CAD-induced cancer cell death and are in line with our previous identification of Ca 2+dependent adenylate cyclase 1 as a mediator of CAD-induced lysosomal membrane permeabilization and cell death 27,34 . Providing further support for a link between the lysosomal P2RX4 Ca 2+ channel and TMEM165-mediated lysosomal H + leakage, a recent report describes a significant, P2RX4-dependent increase in the lysosomal pH in metastatic breast cancer cells 55 , and the expression of both P2RX4 and TMEM165 has been linked to the metastatic potential of breast cancer cells 55,56 .…”

Section: Discussionsupporting

confidence: 90%

TMEM165 replenishes lysosomal Ca²⁺stores, protects cells against Ca²⁺overload, and mediates Ca²⁺-induced lysosomal H⁺leakage

Chen,

Liu,

Jaślan

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The proper function of lysosomes depends on their ability to store and release calcium. While several lysosomal calcium release channels have been described, how mammalian lysosomes replenish their calcium stores has not been determined. Using genetic depletion and overexpression techniques combined with electrophysiology and visualization of subcellular ion concentrations and their fluxes across the lysosomal membrane, we show here that TMEM165 imports calcium to the lysosomal lumen and mediates calcium-induced lysosomal proton leakage. Accordingly, TMEM165 accelerates the recovery of cells from cytosolic calcium overload thereby enhancing cell survival while causing a significant acidification of the perilysosomal area and the entire cytosol. These data indicate that in addition to its essential role in the glycosylation in the Golgi, a small but significant fraction of TMEM165 localizes on the lysosomal limiting membrane, where it protects cells against cytosolic calcium overload, preserves lysosomal function by refilling lysosomal calcium stores and regulates perilysosomal and lysosomal pH.

show abstract

Section: Discussionsupporting

confidence: 90%

TMEM165 replenishes lysosomal Ca²⁺stores, protects cells against Ca²⁺overload, and mediates Ca²⁺-induced lysosomal H⁺leakage

Chen,

Liu,

Jaślan

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…S1B). A propidium iodide (PI) uptake assay measuring plasma membrane integrity(Crowley et al, 2016; Liu et al, 2023) was adapted to quantify cell survival during lysosomal damage using HCM. We found significant cell death upon LLOMe treatment in ΔΔG3BP1/2 cells compared to wildtype (WT) U2OS cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

Duran,

Poolsup,

Allers

et al. 2024

Preprint

View full text Add to dashboard Cite

Lysosomal damage poses a significant threat to cell survival. Our previous work has reported that lysosomal damage induces stress granule (SG) formation. However, the importance of SG formation in determining cell fate and the precise mechanisms through which lysosomal damage triggers SG formation remains unclear. Here, we show that SG formation is initiated via a novel calcium-dependent pathway and plays a protective role in promoting cell survival in response to lysosomal damage. Mechanistically, we demonstrate that during lysosomal damage, ALIX, a calcium-activated protein, transduces lysosomal damage signals by sensing calcium leakage to induce SG formation by controlling the phosphorylation of eIF2α. ALIX modulates eIF2α phosphorylation by regulating the association between PKR and its activator PACT, with galectin-3 exerting a negative effect on this process. We also found this regulatory event of SG formation occur on damaged lysosomes. Collectively, these investigations reveal novel insights into the precise regulation of SG formation triggered by lysosomal damage, and shed light on the interaction between damaged lysosomes and SGs. Importantly, SG formation is significant for promoting cell survival in the physiological context of lysosomal damage inflicted by SARS-CoV-2 ORF3a, adenovirus infection, Malaria hemozoin, proteopathic tau as well as environmental hazard silica.

show abstract

“…Unphosphorylated STAT3 is involved in the regulation of lysosomal function, and excessive nuclear localisation of STAT3 restricts this activity through lowering cytoplasmic STAT3 levels [ 30 , 31 ]. The elevated plasma and CSF levels of pro-inflammatory cytokines in ALS [ 32 , 33 ] are probably responsible for the high nuclear levels of STAT3 observed in post-mortem ALS microglia and astrocytes and in SOD1-G93A mouse motor neurons [ 34 ].…”

Section: Stat3 Signalling In Alsmentioning

confidence: 99%

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis

Richardson,

Smith,

de Giorgio

et al. 2023

Transl Neurodegener

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a poorly treated multifactorial neurodegenerative disease associated with multiple cell types and subcellular organelles. As with other multifactorial diseases, it is likely that drugs will need to target multiple disease processes and cell types to be effective. We review here the role of Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) signalling in ALS, confirm the association of this signalling with fundamental ALS disease processes using the BenevolentAI Knowledge Graph, and demonstrate that inhibitors of this pathway could reduce the ALS pathophysiology in neurons, glia, muscle fibres, and blood cells. Specifically, we suggest that inhibition of the JAK enzymes by approved inhibitors known as Jakinibs could reduce STAT3 activation and modify the progress of this disease. Analysis of the Jakinibs highlights baricitinib as a suitable candidate due to its ability to penetrate the central nervous system and exert beneficial effects on the immune system. Therefore, we recommend that this drug be tested in appropriately designed clinical trials for ALS.

show abstract

Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux

Cited by 9 publications

References 63 publications

TMEM165 replenishes lysosomal Ca²⁺stores, protects cells against Ca²⁺overload, and mediates Ca²⁺-induced lysosomal H⁺leakage

TMEM165 replenishes lysosomal Ca²⁺stores, protects cells against Ca²⁺overload, and mediates Ca²⁺-induced lysosomal H⁺leakage

A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis

Contact Info

Product

Resources

About

Cationic amphiphilic antihistamines inhibit STAT3 via Ca2+-dependent lysosomal H+ efflux

Cited by 9 publications

References 63 publications

TMEM165 replenishes lysosomal Ca2+stores, protects cells against Ca2+overload, and mediates Ca2+-induced lysosomal H+leakage

TMEM165 replenishes lysosomal Ca2+stores, protects cells against Ca2+overload, and mediates Ca2+-induced lysosomal H+leakage

A mechanism that transduces lysosomal damage signals to stress granule formation for cell survival

Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis

Contact Info

Product

Resources

About

TMEM165 replenishes lysosomal Ca²⁺stores, protects cells against Ca²⁺overload, and mediates Ca²⁺-induced lysosomal H⁺leakage

TMEM165 replenishes lysosomal Ca²⁺stores, protects cells against Ca²⁺overload, and mediates Ca²⁺-induced lysosomal H⁺leakage