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Progranulin associates with Rab2 and is involved in autophagosome-lysosome fusion in Gaucher disease

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Abstract

Progranulin (PGRN) is a key regulator of lysosomes, and its deficiency has been linked to various lysosomal storage diseases (LSDs), including Gaucher disease (GD), one of the most common LSD. Here, we report that PGRN plays a previously unrecognized role in autophagy within the context of GD. PGRN deficiency is associated with the accumulation of LC3-II and p62 in autophagosomes of GD animal model and patient fibroblasts, resulting from the impaired fusion of autophagosomes and lysosomes. PGRN physically interacted with Rab2, a critical molecule in autophagosome-lysosome fusion. Additionally, a fragment of PGRN containing the Grn E domain was required and sufficient for binding to Rab2. Furthermore, this fragment significantly ameliorated PGRN deficiency–associated impairment of autophagosome-lysosome fusion and autophagic flux. These findings not only demonstrate that PGRN is a crucial mediator of autophagosome-lysosome fusion but also provide new evidence indicating PGRN’s candidacy as a molecular target for modulating autophagy in GD and other LSDs in general.

Key messages

  • PGRN acts as a crucial factor involved in autophagosome-lysosome fusion in GD.

  • PGRN physically interacts with Rab2, a molecule in autophagosome-lysosome fusion.

  • A 15-kDa C-terminal fragment of PGRN is required and sufficient for binding to Rab2.

  • This PGRN derivative ameliorates PGRN deficiency–associated impairment of autophagy.

  • This study provides new insights into autophagy and may develop novel therapy for GD.

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References

  1. Glick D, Barth S, Macleod KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221(1):3–12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Settembre C et al (2008) Lysosomal storage diseases as disorders of autophagy. Autophagy 4(1):113–114

    Article  PubMed  Google Scholar 

  3. Kinghorn KJ, Asghari AM, Castillo-Quan JI (2017) The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson’s disease. Neural Regen Res 12(3):380–384

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Seranova E et al (2017) Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. Essays Biochem 61(6):733–749

    Article  PubMed  PubMed Central  Google Scholar 

  5. Platt FM (2014) Sphingolipid lysosomal storage disorders. Nature 510(7503):68–75

    Article  PubMed  CAS  Google Scholar 

  6. Chen Y et al (2018) Molecular regulations and therapeutic targets of Gaucher disease. Cytokine Growth Factor Rev 41:65–74

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Grabowski GA (2012) Gaucher disease and other storage disorders. Hematology Am Soc Hematol Educ Program 2012:13–18

    Article  PubMed  Google Scholar 

  8. Pitcairn C, Wani WY, Mazzulli JR (2019) Dysregulation of the autophagic-lysosomal pathway in Gaucher and Parkinson’s disease. Neurobiol Dis 122:72–82

    Article  PubMed  CAS  Google Scholar 

  9. Sun Y, Grabowski GA (2010) Impaired autophagosomes and lysosomes in neuronopathic Gaucher disease. Autophagy 6(5):648–649

    Article  PubMed  Google Scholar 

  10. Li H et al (2019) Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations. Autophagy 15(1):113–130

    Article  PubMed  CAS  Google Scholar 

  11. Moren C et al (2019) GBA mutation promotes early mitochondrial dysfunction in 3D neurosphere models. Aging (Albany NY) 11(22):10338–10355

    Article  CAS  Google Scholar 

  12. Li SS et al (2019) Reduction of PGRN increased fibrosis during skin wound healing in mice. Histol Histopathol 34(7):765–774

    PubMed  Google Scholar 

  13. Jian J, Konopka J, Liu C (2013) Insights into the role of progranulin in immunity, infection, and inflammation. J Leukoc Biol 93(2):199–208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Jian J et al (2016) Progranulin recruits HSP70 to beta-glucocerebrosidase and is therapeutic against Gaucher disease. EBioMedicine 13:212–224

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jian J et al (2018) Progranulin: a key player in autoimmune diseases. Cytokine 101:48–55

    Article  PubMed  CAS  Google Scholar 

  16. Bateman A, Bennett HP (2009) The granulin gene family: from cancer to dementia. BioEssays 31(11):1245–1254

    Article  PubMed  CAS  Google Scholar 

  17. Cui Y, Hettinghouse A, Liu CJ (2019) Progranulin: a conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases. Cytokine Growth Factor Rev 45:53–64

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Bateman A, Cheung ST, Bennett HPJ (2018) A brief overview of progranulin in health and disease. Methods Mol Biol 1806:3–15

    Article  PubMed  CAS  Google Scholar 

  19. Baker M et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442(7105):916–919

    Article  PubMed  CAS  Google Scholar 

  20. Arrant AE et al (2017) Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia. Brain 140(5):1447–1465

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gotzl JK et al (2014) Common pathobiochemical hallmarks of progranulin-associated frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis. Acta Neuropathol 127(6):845–860

    PubMed  Google Scholar 

  22. Mendsaikhan A, Tooyama I, Walker DG (2019) Microglial progranulin: involvement in Alzheimer’s disease and neurodegenerative diseases. Cells  8(3)

  23. Chitramuthu BP, Bennett HPJ, Bateman A (2017) Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain 140(12):3081–3104

    Article  PubMed  Google Scholar 

  24. Tang W et al (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332(6028):478–484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Jian J et al (2013) Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains. FEBS Lett 587(21):3428–3436

    Article  PubMed  CAS  Google Scholar 

  26. Liu C et al (2014) Progranulin-derived Atsttrin directly binds to TNFRSF25 (DR3) and inhibits TNF-like ligand 1A (TL1A) activity. PLoS One 9(3): p. e92743

  27. Li M et al (2014) Progranulin is required for proper ER stress response and inhibits ER stress-mediated apoptosis through TNFR2. Cell Signal 26(7):1539–1548

    Article  PubMed  CAS  Google Scholar 

  28. Chang MC et al (2017) Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation. J Exp Med 214(9):2611–2628

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Guo Q et al (2017) Progranulin causes adipose insulin resistance via increased autophagy resulting from activated oxidative stress and endoplasmic reticulum stress. Lipids Health Dis 16(1):25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Zhou B et al (2015) Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice. J Mol Endocrinol 55(3):231–243

    Article  PubMed  CAS  Google Scholar 

  31. Liu J et al (2015) PGRN induces impaired insulin sensitivity and defective autophagy in hepatic insulin resistance. Mol Endocrinol 29(4):528–541

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Jian J et al (2016) Association between progranulin and Gaucher disease. EBioMedicine 11:127–137

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chen Y et al (2018) Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease. J Mol Med (Berl) 96(12):1359–1373

    Article  CAS  Google Scholar 

  34. Elia LP et al (2019) Genetic regulation of neuronal progranulin reveals a critical role for the autophagy-lysosome pathway. J Neurosci 39(17):3332–3344

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Coffey EE et al (2014) Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer’s disease-linked presenilin 1 A246E mutation can be reversed with cAMP. Neuroscience 263:111–124

    Article  PubMed  CAS  Google Scholar 

  36. K Castillo et al (2013) Measurement of autophagy flux in the nervous system in vivo. Cell Death and Disease 4: p. e917

  37. Shi H et al (2017) Na+/H+ exchanger regulates amino acid-mediated autophagy in intestinal epithelial cells. Cell Physiol Biochem 42:2418–2429

    Article  PubMed  CAS  Google Scholar 

  38. Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12(9):831–835

    Article  PubMed  CAS  Google Scholar 

  39. Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20(3):460–473

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Mizushima N (2020) The ATG conjugation systems in autophagy. Curr Opin Cell Biol 63:1–10

    Article  PubMed  CAS  Google Scholar 

  41. Romanov J et al (2012) Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation. EMBO J 31(22):4304–4317

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Chen M et al (2016) TRIM14 inhibits cGAS degradation mediated by selective autophagy receptor p62 to promote innate immune responses. Mol Cell 64(1):105–119

    Article  PubMed  CAS  Google Scholar 

  43. Lamark T, Svenning S, Johansen T (2017) Regulation of selective autophagy: the p62/SQSTM1 paradigm. Essays Biochem 61(6):609–624

    Article  PubMed  Google Scholar 

  44. Danieli A, Martens S (2018) p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy. J Cell Sci 131(19)

  45. Yoshii SR, Mizushima N (2017) Monitoring and measuring autophagy. Int J Mol Sci 18(9)

  46. Eskelinen EL (2005) Maturation of autophagic vacuoles in mammalian cells. Autophagy 1(1):1–10

    Article  PubMed  CAS  Google Scholar 

  47. Settembre C et al (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17(1):119–129

    Article  PubMed  CAS  Google Scholar 

  48. Matus S, Valenzuela V, Hetz C (2014) A new method to measure autophagy flux in the nervous system. Autophagy 10(4):710–714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. von Muhlinen N (2019) Methods to measure autophagy in cancer metabolism. Methods Mol Biol 1928:149–173

    Article  CAS  Google Scholar 

  50. Tanaka Y et al (2017) Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. Hum Mol Genet 26(5):969–988

    PubMed  CAS  Google Scholar 

  51. Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: cellular and molecular mechanisms. Autophagy 14(2):207–215

    Article  PubMed  CAS  Google Scholar 

  52. Chen Y, Yu L (2018) Development of research into autophagic lysosome reformation. Mol Cells 41(1):45–49

    PubMed  PubMed Central  CAS  Google Scholar 

  53. Itakura E, Kishi-Itakura C, Mizushima N (2012) The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151(6):1256–1269

    Article  PubMed  CAS  Google Scholar 

  54. Takats S et al (2018) Small GTPases controlling autophagy-related membrane traffic in yeast and metazoans. Small GTPases 9(6):465–471

    Article  PubMed  CAS  Google Scholar 

  55. Nakamura S, Yoshimori T (2017) New insights into autophagosome-lysosome fusion. J Cell Sci 130(7):1209–1216

    PubMed  CAS  Google Scholar 

  56. Kuchitsu Y, Fukuda M (2018) Revisiting Rab7 functions in mammalian autophagy: Rab7 Knockout Studies. Cells 7(11)

  57. Jager S et al (2004) Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 117(Pt 20):4837–4848

    Article  PubMed  CAS  Google Scholar 

  58. Ding X et al (2019) RAB2 regulates the formation of autophagosome and autolysosome in mammalian cells. Autophagy 15(10):1774–1786

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lorincz P et al (2017) Rab2 promotes autophagic and endocytic lysosomal degradation. J Cell Biol 216(7):1937–1947

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Lund VK, Madsen KL, Kjaerulff O (2018) Drosophila Rab2 controls endosome-lysosome fusion and LAMP delivery to late endosomes. Autophagy 14(9):1520–1542

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Fujita N et al (2017) Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy. Elife 6

  62. Altmann C et al (2016) Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy. Neurobiol Dis 96:294–311

    Article  PubMed  CAS  Google Scholar 

  63. Feng T et al (2016) Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway. Oncotarget 7(36):58381–58395

    Article  PubMed  PubMed Central  Google Scholar 

  64. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960–976

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Codogno P, Meijer AJ (2005) Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12(Suppl 2):1509–1518

    Article  PubMed  CAS  Google Scholar 

  66. Noda T (2017) Regulation of autophagy through TORC1 and mTORC1. Biomolecules 7(3)

  67. Lorincz, P, Juhasz G (2019) Autophagosome-lysosome fusion. J Mol Biol

  68. Eskelinen EL (2008) To be or not to be? Examples of incorrect identification of autophagic compartments in conventional transmission electron microscopy of mammalian cells. Autophagy 4(2):257–260

    Article  PubMed  Google Scholar 

  69. Reddy PH (2011) Mitochondrial dysfunction and oxidative stress in asthma: implications for mitochondria-targeted antioxidant therapeutics. Pharmaceuticals (Basel) 4(3):429–456

    Article  CAS  Google Scholar 

  70. Sachdeva K et al (2019) Environmental exposures and asthma development: autophagy, mitophagy, and cellular senescence. Front Immunol 10:2787

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Garza-Lombo C et al (2020) Redox homeostasis, oxidative stress and mitophagy. Mitochondrion 51:105–117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Kanki T et al (2009) Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell 17(1):98–109

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Kinya O et al (2015) BCL2L13 is a mammalian homolog of the yeast mitophagy receptor Atg32. Autophgy p. 1932–1933

  74. Gegg ME, Schapira AH (2016) Mitochondrial dysfunction associated with glucocerebrosidase deficiency. Neurobiol Dis 90:43–50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Osellame LD, Duchen MR (2013) Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. Autophagy 9(10):1633–1635

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Drs. Yan Deng and Fengxia Liang at NYU Medical School OCS Microscopy Core for their assistance with confocal and electronic microscope images. We also thank all lab members for the insightful discussions. Patents have been filed by NYU that claim PGRN and its derivatives for the diagnosis and treatment of Gaucher disease (PCT/US2015014364).

Funding

This work was supported partly by NIH research grants R01NS103931, R01AR062207, R01AR061484, and R01AR076900.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, New York University Medical Center, Rm 1608, LOH, 301 East 17th Street, New York, NY, 10003, USA

    Xiangli Zhao, Rossella Liberti, Jinlong Jian, Wenyu Fu, Aubryanna Hettinghouse & Chuan-ju Liu

  2. Division of Human Genetics, The Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

    Ying Sun

  3. Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, 10016, USA

    Chuan-ju Liu

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  1. Xiangli Zhao
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  2. Rossella Liberti
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  3. Jinlong Jian
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  4. Wenyu Fu
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  5. Aubryanna Hettinghouse
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  6. Ying Sun
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Contributions

X. Zhao, J. Jian, R. Liberti, and W. Fu designed and performed experiments, collected and analyzed data, and wrote the paper. A. Hettinghouse assisted with experiments and editing the manuscript. Y. Sun contributed to the conceptualization and data interpretation. C. J. Liu supervised this study, analyzed data, and co-wrote and edited the manuscript.

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Correspondence to Chuan-ju Liu.

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Zhao, X., Liberti, R., Jian, J. et al. Progranulin associates with Rab2 and is involved in autophagosome-lysosome fusion in Gaucher disease. J Mol Med 99, 1639–1654 (2021). https://doi.org/10.1007/s00109-021-02127-6

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  • DOI: https://doi.org/10.1007/s00109-021-02127-6

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