Tubular Lysosomes Harbor Active Ion Gradients and Poise Macrophages for Phagocytosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Oct 5

PMID 34607961

Citations 17

Authors

Bhavyashree Suresh

Anand Saminathan

Kasturi Chakraborty

Matthew Zajac

Chang Cui

Lev Becker

Yamuna Krishnan

Affiliations

Soon will be listed here.

Abstract

Lysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution, and autophagy. Tubular lysosomes are studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the biochemical properties lysosomes acquire upon tubulation that could drive their functionality. Here we describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Proteolytic activity maps at single-lysosome resolution revealed that tubular lysosomes were less degradative and showed proximal to distal luminal pH and Ca gradients. Such gradients had been predicted but never previously observed. We identify a role for tubular lysosomes in promoting phagocytosis and activating MMP9. The ability to tubulate lysosomes without starving or activating immune cells may help reveal new roles for tubular lysosomes.

Citing Articles

Targeted imaging of lysosomal zinc ions with a tetrahedral DNA framework fluorescent reporter.

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Mechanisms of lysosomal tubulation and sorting driven by LRRK2.

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Pressure sensing of lysosomes enables control of TFEB responses in macrophages.

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The ion channels of endomembranes.

Hu M, Feng X, Liu Q, Liu S, Huang F, Xu H Physiol Rev. 2024; 104(3):1335-1385.

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A mechanism of lysosomal calcium entry.

Zajac M, Mukherjee S, Anees P, Oettinger D, Henn K, Srikumar J Sci Adv. 2024; 10(7):eadk2317.

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References

Kong D, Yamori T . ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system. Acta Pharmacol Sin. 2010; 31(9):1189-97. PMC: 4002321. DOI: 10.1038/aps.2010.150. View

Chan Y, Cardwell M, Hermanas T, Uchiyama T, Martinez J . Rickettsial outer-membrane protein B (rOmpB) mediates bacterial invasion through Ku70 in an actin, c-Cbl, clathrin and caveolin 2-dependent manner. Cell Microbiol. 2009; 11(4):629-44. PMC: 2773465. DOI: 10.1111/j.1462-5822.2008.01279.x. View

Cabukusta B, Neefjes J . Mechanisms of lysosomal positioning and movement. Traffic. 2018; 19(10):761-769. PMC: 6175085. DOI: 10.1111/tra.12587. View

Kaniuk N, Canadien V, Bagshaw R, Bakowski M, Braun V, Landekic M . Salmonella exploits Arl8B-directed kinesin activity to promote endosome tubulation and cell-to-cell transfer. Cell Microbiol. 2011; 13(11):1812-23. DOI: 10.1111/j.1462-5822.2011.01663.x. View

Lacombe J, Karsenty G, Ferron M . Regulation of lysosome biogenesis and functions in osteoclasts. Cell Cycle. 2013; 12(17):2744-52. PMC: 3899188. DOI: 10.4161/cc.25825. View

Munson M, Allen G, Toth R, Campbell D, Lucocq J, Ganley I . mTOR activates the VPS34-UVRAG complex to regulate autolysosomal tubulation and cell survival. EMBO J. 2015; 34(17):2272-90. PMC: 4585463. DOI: 10.15252/embj.201590992. View

Cheng C, Hsieh H, Hsiao L, Yang C . PI3-K/Akt/JNK/NF-κB is essential for MMP-9 expression and outgrowth in human limbal epithelial cells on intact amniotic membrane. Stem Cell Res. 2012; 9(1):9-23. DOI: 10.1016/j.scr.2012.02.005. View

Saha S, Prakash V, Halder S, Chakraborty K, Krishnan Y . A pH-independent DNA nanodevice for quantifying chloride transport in organelles of living cells. Nat Nanotechnol. 2015; 10(7):645-51. DOI: 10.1038/nnano.2015.130. View

Monferran S, Paupert J, Dauvillier S, Salles B, Muller C . The membrane form of the DNA repair protein Ku interacts at the cell surface with metalloproteinase 9. EMBO J. 2004; 23(19):3758-68. PMC: 522801. DOI: 10.1038/sj.emboj.7600403. View

10.

Yang J, Zhao Z, Gu M, Feng X, Xu H . Release and uptake mechanisms of vesicular Ca stores. Protein Cell. 2018; 10(1):8-19. PMC: 6321814. DOI: 10.1007/s13238-018-0523-x. View

11.

Jani M, Zou J, Veetil A, Krishnan Y . A DNA-based fluorescent probe maps NOS3 activity with subcellular spatial resolution. Nat Chem Biol. 2020; 16(6):660-666. DOI: 10.1038/s41589-020-0491-3. View

12.

Van Maanen J, Retel J, de Vries J, Pinedo H . Mechanism of action of antitumor drug etoposide: a review. J Natl Cancer Inst. 1988; 80(19):1526-33. DOI: 10.1093/jnci/80.19.1526. View

13.

Li X, Rydzewski N, Hider A, Zhang X, Yang J, Wang W . A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol. 2016; 18(4):404-17. PMC: 4871318. DOI: 10.1038/ncb3324. View

14.

Sun Y, Li M, Zhao D, Li X, Yang C, Wang X . Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in . Elife. 2020; 9. PMC: 7274789. DOI: 10.7554/eLife.55745. View

15.

Saminathan A, Devany J, Veetil A, Suresh B, Smitha Pillai K, Schwake M . A DNA-based voltmeter for organelles. Nat Nanotechnol. 2020; 16(1):96-103. PMC: 8513801. DOI: 10.1038/s41565-020-00784-1. View

16.

Johnson A, Shu H, Hauswirth A, Tong A, Davis G . VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo. Elife. 2015; 4. PMC: 4574298. DOI: 10.7554/eLife.07366. View

17.

Shihab P, Al-Roub A, Al-Ghanim M, Al-Mass A, Behbehani K, Ahmad R . TLR2 and AP-1/NF-kappaB are involved in the regulation of MMP-9 elicited by heat killed Listeria monocytogenes in human monocytic THP-1 cells. J Inflamm (Lond). 2015; 12:32. PMC: 4415258. DOI: 10.1186/s12950-015-0077-0. View

18.

Tan T, Zheng G, Hsu T, Lee S, Zhang J, Zhao Y . Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage. Lab Invest. 2013; 93(4):434-49. DOI: 10.1038/labinvest.2013.3. View

19.

Yamada O, Ozaki K, Akiyama M, Kawauchi K . JAK-STAT and JAK-PI3K-mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells. Mol Cancer Ther. 2012; 11(5):1112-21. DOI: 10.1158/1535-7163.MCT-11-0850. View

20.

Guilliams M, Ginhoux F, Jakubzick C, Naik S, Onai N, Schraml B . Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol. 2014; 14(8):571-8. PMC: 4638219. DOI: 10.1038/nri3712. View