Macropinosome Explained

Macropinosomes are a type of cellular compartment that form as a result of macropinocytosis.

Formation

Macropinosomes have been described to form via a wave-like mechanism[1] or via a tent-pole formation[2] both of which processes require rapid polymerisation of actin-rich structures that rise up from the cell surface before collapsing back down into a macropinosome.

Function

Macropinosomes serve primarily in the uptake of solutes from the extracellular fluid.[3] [4] Once inside the cell, macropinosomes undergo a process of maturation characterized by increasing expression of Rab7 as they progress through the endocytic pathway, until they fuse with lysosomes where the contents of the macropinosome are degraded.[5]

Regulation

PI3K and phosphoinositide phospholipase C activation have been shown to be necessary for macropinosome formation in fibroblasts.[6] Members of the SNX family have also been shown to be important in macropinosome formation.[7] Conversely, cyclic AMP has been shown to promote regurgitation from macropinosomes.[8]

Role in pathogenesis

Because the process of macropinocytosis is non-specific, many pathogens take advantage of macropinosomes to infect their target cells. In this way, pathogens internalized in macropinosomes avoid barriers and obstructions that the plasma membrane, cytoplasmic crowding and cortical cytoskeleton pose when moving deeper into the cytoplasm. One example is Zaire ebolavirus, responsible for the devastating ebola virus disease, which stimulates macropinosome formation upon binding to the target cell surface.[9] Vaccinia virus (VACV), a member of Poxviridae family, has also been shown to partially utilize macropinocytosis for infectious cell entry. Here, both infectious forms of VACV, mature virion (MV) and enveloped virion (EV), induce their own macropinocytosis by binding to the cell surface and triggering an actin-mediated plasma membrane protrusion that eventually collapses back onto the plasma membrane sealing the attached virion inside a macropinosome, which then goes through a maturation program that leads to core activation and genome release.[10] Shiga toxin produced by enterohemorrhagic E. coli has been shown to enter target cells via macropinocytosis, causing gastrointestinal tract complications.[11] Other pathogens that have been shown to utilize this mechanism are Kaposi's sarcoma-associated herpesvirus[12] and Salmonella.[13]

Notes and References

  1. Mercer. Jason. Helenius. Ari. 2009. Virus entry by macropinocytosis. Nature Cell Biology. En. 11. 5. 510–520. 10.1038/ncb0509-510. 19404330. 205286378. 1465-7392.
  2. Condon. Nicholas D.. Heddleston. John M.. Chew. Teng-Leong. Luo. Lin. McPherson. Peter S.. Ioannou. Maria S.. Hodgson. Louis. Jennifer Stow. Stow, Jennifer L.. Wall. Adam A.. 2018-08-27. Macropinosome formation by tent pole ruffling in macrophages. J Cell Biol. 217. 11. en. 3873–3885. 10.1083/jcb.201804137. 0021-9525. 30150290. 6219714.
  3. Racoosin. E. L.. Swanson. J. A.. 1992. M-CSF-induced macropinocytosis increases solute endocytosis but not receptor-mediated endocytosis in mouse macrophages. Journal of Cell Science. 102. 4. 867–880. 10.1242/jcs.102.4.867. 1429898.
  4. Hacker. U.. Albrecht. R.. Maniak. M.. 1997. Fluid-phase uptake by macropinocytosis in Dictyostelium. Journal of Cell Science. 110. 2. 105–112. 10.1242/jcs.110.2.105. 9044041.
  5. Racoosin. E. L.. Swanson. J. A.. 1993. Macropinosome maturation and fusion with tubular lysosomes in macrophages. The Journal of Cell Biology. 121. 5. 1011–1020. 10.1083/jcb.121.5.1011. 2119679. 8099075.
  6. Amyere . M. . Payrastre . B. . Krause . U. . Van Der Smissen . P. . Veithen . A. . Courtoy . P. J. . Constitutive Macropinocytosis in Oncogene-transformed Fibroblasts Depends on Sequential Permanent Activation of Phosphoinositide 3-Kinase and Phospholipase C . Molecular Biology of the Cell . 11 . 10 . 3453–3467 . 2000 . 11029048 . 15006 . 10.1091/mbc.11.10.3453.
  7. Wang . J. T. H. . Kerr . M. C. . Karunaratne . S. . Jeanes . A. . Yap . A. S. . Teasdale . R. D. . Caplan . Steve H. . The SNX-PX-BAR Family in Macropinocytosis: The Regulation of Macropinosome Formation by SNX-PX-BAR Proteins . 10.1371/journal.pone.0013763 . PLOS ONE . 5 . 10 . e13763 . 2010 . 21048941 . 2966440 . 2010PLoSO...513763W . free .
  8. Veithen . A. . Amyere . M. . Van Der Smissen . P. . Cupers . P. . Courtoy . P. J. . Regulation of macropinocytosis in v-Src-transformed fibroblasts: Cyclic AMP selectively promotes regurgitation of macropinosomes . Journal of Cell Science . 111 . 2329–2335 . 1998 . 9683628 . 16. 10.1242/jcs.111.16.2329 .
  9. Saeed . M. F. . Kolokoltsov . A. A. . Albrecht . T. . Davey . R. A. . Basler . Christopher F. . Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes . 10.1371/journal.ppat.1001110 . PLOS Pathogens . 6 . 9 . e1001110 . 2010 . 20862315 . 2940741 . free .
  10. Rizopoulos Z, Balistreri G, Kilcher S, Martin CK, Syedbasha M, Helenius A, Mercer J. Vaccinia Virus Infection Requires Maturation of Macropinosomes. Traffic. 2015 Aug;16(8):814-31. doi: 10.1111/tra.12290. Epub 2015 May 6. PMID 25869659; PMCID: PMC4973667.
  11. Lukyanenko . V. . Malyukova . I. . Hubbard . A. . Delannoy . M. . Boedeker . E. . Zhu . C. . Cebotaru . L. . Kovbasnjuk . O. . Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells . 10.1152/ajpcell.00036.2011 . AJP: Cell Physiology . 301 . 5 . C1140–C1149 . 3213915 . 2011 . 21832249.
  12. Valiya Veettil . M. . Sadagopan . S. . Kerur . N. . Chakraborty . S. . Chandran . B. . Früh . Klaus . Interaction of c-Cbl with Myosin IIA Regulates Bleb Associated Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus . 10.1371/journal.ppat.1001238 . PLOS Pathogens . 6 . 12 . e1001238 . 2010 . 21203488 . 3009604 . free .
  13. Kerr . M. C. . Wang . J. T. H. . Castro . N. A. . Hamilton . N. A. . Town . L. . Brown . D. L. . Meunier . F. A. . Brown . N. F. . Stow . J. L. . 10.1038/emboj.2010.28 . Teasdale . R. D. . Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella . The EMBO Journal . 29 . 8 . 1331–1347 . 2010 . 20300065 . 2868569 .

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