ArticlePLoS biology2019
Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR.
Article in PLoS biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
60 citing papers in PubMed, 105 citations in OpenAlex.
- Calcium and TRPML-Mediated Autophagy: Implications in Cancer, Cardiovascular Diseases, and Cardio-Oncology.Cardiovascular toxicology · 2026Review
- The nonexcitable smooth muscle: remodeling the smooth muscle ion transport toolkit in disease.Physiological reviews · 2026Review
- TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.Nature communications · 2026Article
- DNA nanodevices detect an acidic nanolayer on the lysosomal surface.Nature cell biology · 2026Article
- [Single-cell RNA sequencing of B cells reveals molecular typing in Sjögren syndrome].Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences · 2025Article
- Lysosomal and mTORC1 signaling dysregulation underpin the pathology of spastic paraplegia type 80.Nature communications · 2025Article
- Lysosomal CaCirculation. Arrhythmia and electrophysiology · 2025Article
- Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants.eLife · 2025Article
- Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.Aging and disease · 2025Review
- Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress.The Journal of cell biology · 2025Article
- Article
- TRPML1 gating modulation by allosteric mutations and lipids.bioRxiv : the preprint server for biology · 2024Article
- Activation of the TRPML1 Ion Channel Induces Proton Secretion in the Human Gastric Parietal Cell Line HGT-1.International journal of molecular sciences · 2024Article
- The ion channels of endomembranes.Physiological reviews · 2024Review
- CaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- LAMTOR1 regulates dendritic lysosomal positioning in hippocampal neurons through TRPML1 inhibition.Frontiers in cellular neuroscience · 2024Article
- Tamoxifen Activates Transcription Factor EB and Triggers Protective Autophagy in Breast Cancer Cells by Inducing Lysosomal Calcium Release: A Gateway to the Onset of Endocrine Resistance.International journal of molecular sciences · 2023Article
- Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.Aging · 2023Article
- TRPML3/BK complex promotes autophagy and bacterial clearance by providing a positive feedback regulation of mTOR via PI3P.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Unbiased evaluation of rapamycin's specificity as an mTOR inhibitor.Aging cell · 2023Article
Corrections and comments
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Authors and funding
19 authors at 4 institutions in 3 countries.
Funding
Abstract
Rapamycin (Rap) and its derivatives, called rapalogs, are being explored in clinical trials targeting cancer and neurodegeneration. The underlying mechanisms of Rap actions, however, are not well understood. Mechanistic target of rapamycin (mTOR), a lysosome-localized protein kinase that acts as a critical regulator of cellular growth, is believed to mediate most Rap actions. Here, we identified mucolipin 1 (transient receptor potential channel mucolipin 1 [TRPML1], also known as MCOLN1), the principle Ca2+ release channel in the lysosome, as another direct target of Rap. Patch-clamping of isolated lysosomal membranes showed that micromolar concentrations of Rap and some rapalogs activated lysosomal TRPML1 directly and specifically. Pharmacological inhibition or genetic inactivation of mTOR failed to mimic the Rap effect. In vitro binding assays revealed that Rap bound directly to purified TRPML1 proteins with a micromolar affinity. In both healthy and disease human fibroblasts, Rap and rapalogs induced autophagic flux via nuclear translocation of transcription factor EB (TFEB). However, such effects were abolished in TRPML1-deficient cells or by TRPML1 inhibitors. Hence, Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.