Lysosomal Adaptation: How the Lysosome Responds to External Cues

Overview

Journal Cold Spring Harb Perspect Biol

Specialties Biology
Molecular Biology

Date 2014 May 7

PMID 24799353

Citations 57

Authors

Carmine Settembre

Andrea Ballabio

Affiliations

Soon will be listed here.

Abstract

Recent evidence indicates that the importance of the lysosome in cell metabolism and organism physiology goes far beyond the simple disposal of cellular garbage. This dynamic organelle is situated at the crossroad of the most important cellular pathways and is involved in sensing, signaling, and transcriptional mechanisms that respond to environmental cues, such as nutrients. Two main mediators of these lysosomal adaptation mechanisms are the mTORC1 kinase complex and the transcription factor EB (TFEB). These two factors are linked in a lysosome-to-nucleus signaling pathway that provides the lysosome with the ability to adapt to extracellular cues and control its own biogenesis. Modulation of lysosomal function by acting on TFEB has a profound impact on cellular clearance and energy metabolism and is a promising therapeutic target for a large variety of disease conditions.

Citing Articles

TIGAR coordinates senescence-associated secretory phenotype via lysosome repositioning and α-tubulin deacetylation.

Nam H, Park S, Lee G, Kim E, Lee S, Chang H Exp Mol Med. 2024; 56(12):2726-2738.

PMID: 39633033 PMC: 11671532. DOI: 10.1038/s12276-024-01362-4.

Failure of Autophagy in Pompe Disease.

Do H, Meena N, Raben N Biomolecules. 2024; 14(5).

PMID: 38785980 PMC: 11118179. DOI: 10.3390/biom14050573.

Glucose starvation causes ferroptosis-mediated lysosomal dysfunction.

Miki K, Yagi M, Kang D, Kunisaki Y, Yoshimoto K, Uchiumi T iScience. 2024; 27(5):109735.

PMID: 38706843 PMC: 11067335. DOI: 10.1016/j.isci.2024.109735.

Morquio A Syndrome: Identification of Differential Patterns of Molecular Pathway Interactions in Bone Lesions.

Alvarez J, Bravo S, Chantada-Vazquez M, Pena C, Colon C, Tomatsu S Int J Mol Sci. 2024; 25(6).

PMID: 38542208 PMC: 10970612. DOI: 10.3390/ijms25063232.

Targeting Lysosomes: A Strategy Against Chemoresistance in Cancer.

Shirbhate E, Singh V, Mishra A, Jahoriya V, Veerasamy R, Tiwari A Mini Rev Med Chem. 2024; 24(15):1449-1468.

PMID: 38343053 DOI: 10.2174/0113895575287242240129120002.

References

He C, Klionsky D . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67-93. PMC: 2831538. DOI: 10.1146/annurev-genet-102808-114910. View

Steingrimsson E, Copeland N, Jenkins N . Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet. 2004; 38:365-411. DOI: 10.1146/annurev.genet.38.072902.092717. View

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon J . Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet. 2003; 72(3):722-7. PMC: 1180247. DOI: 10.1086/367847. View

Sorrentino N, DOrsi L, Sambri I, Nusco E, Monaco C, Spampanato C . A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA. EMBO Mol Med. 2013; 5(5):675-90. PMC: 3662312. DOI: 10.1002/emmm.201202083. View

Sancak Y, Bar-Peled L, Zoncu R, Markhard A, Nada S, Sabatini D . Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010; 141(2):290-303. PMC: 3024592. DOI: 10.1016/j.cell.2010.02.024. View

Conner S, Schmid S . Regulated portals of entry into the cell. Nature. 2003; 422(6927):37-44. DOI: 10.1038/nature01451. View

Sardiello M, Palmieri M, di Ronza A, Medina D, Valenza M, Gennarino V . A gene network regulating lysosomal biogenesis and function. Science. 2009; 325(5939):473-7. DOI: 10.1126/science.1174447. View

Rabinowitz J, White E . Autophagy and metabolism. Science. 2010; 330(6009):1344-8. PMC: 3010857. DOI: 10.1126/science.1193497. View

10.

Sun B, Zhou Y, Halabisky B, Lo I, Cho S, Mueller-Steiner S . Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron. 2008; 60(2):247-57. PMC: 2755563. DOI: 10.1016/j.neuron.2008.10.001. View

11.

Roczniak-Ferguson A, Petit C, Froehlich F, Qian S, Ky J, Angarola B . The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012; 5(228):ra42. PMC: 3437338. DOI: 10.1126/scisignal.2002790. View

12.

Rubinsztein D, Marino G, Kroemer G . Autophagy and aging. Cell. 2011; 146(5):682-95. DOI: 10.1016/j.cell.2011.07.030. View

13.

Lieberman A, Puertollano R, Raben N, Slaugenhaupt S, Walkley S, Ballabio A . Autophagy in lysosomal storage disorders. Autophagy. 2012; 8(5):719-30. PMC: 3378416. DOI: 10.4161/auto.19469. View

14.

Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P . Pathogenic lysosomal depletion in Parkinson's disease. J Neurosci. 2010; 30(37):12535-44. PMC: 6633458. DOI: 10.1523/JNEUROSCI.1920-10.2010. View

15.

Steingrimsson E, Tessarollo L, Pathak B, Hou L, Arnheiter H, Copeland N . Mitf and Tfe3, two members of the Mitf-Tfe family of bHLH-Zip transcription factors, have important but functionally redundant roles in osteoclast development. Proc Natl Acad Sci U S A. 2002; 99(7):4477-82. PMC: 123673. DOI: 10.1073/pnas.072071099. View

16.

Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T . The role of autophagy during the early neonatal starvation period. Nature. 2004; 432(7020):1032-6. DOI: 10.1038/nature03029. View

17.

Sagne C, Gasnier B . Molecular physiology and pathophysiology of lysosomal membrane transporters. J Inherit Metab Dis. 2008; 31(2):258-66. DOI: 10.1007/s10545-008-0879-9. View

18.

Mazzulli J, Xu Y, Sun Y, Knight A, McLean P, Caldwell G . Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011; 146(1):37-52. PMC: 3132082. DOI: 10.1016/j.cell.2011.06.001. View

19.

Cang C, Zhou Y, Navarro B, Seo Y, Aranda K, Shi L . mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell. 2013; 152(4):778-790. PMC: 3908667. DOI: 10.1016/j.cell.2013.01.023. View

20.

Chieregatti E, Meldolesi J . Regulated exocytosis: new organelles for non-secretory purposes. Nat Rev Mol Cell Biol. 2005; 6(2):181-7. DOI: 10.1038/nrm1572. View