Macropinosome

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

Contents

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. [1] One example is Ebola virus, 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 poxvirus 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. [1] [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]

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References

  1. 1 2 3 Mercer, Jason; Helenius, Ari (2009). "Virus entry by macropinocytosis". Nature Cell Biology. 11 (5): 510–520. doi:10.1038/ncb0509-510. ISSN   1465-7392. PMID   19404330. S2CID   205286378.
  2. ↑ Condon, Nicholas D.; Heddleston, John M.; Chew, Teng-Leong; Luo, Lin; McPherson, Peter S.; Ioannou, Maria S.; Hodgson, Louis; Stow, Jennifer L.; Wall, Adam A. (2018-08-27). "Macropinosome formation by tent pole ruffling in macrophages". J Cell Biol. 217 (11): 3873–3885. doi:10.1083/jcb.201804137. ISSN   0021-9525. PMC   6219714 . PMID   30150290.
  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. doi:10.1242/jcs.102.4.867. PMID   1429898.
  4. ↑ Hacker, U.; Albrecht, R.; Maniak, M. (1997). "Fluid-phase uptake by macropinocytosis in Dictyostelium". Journal of Cell Science. 110 (2): 105–112. doi:10.1242/jcs.110.2.105. PMID   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. doi:10.1083/jcb.121.5.1011. PMC   2119679 . PMID   8099075.
  6. ↑ Amyere, M.; Payrastre, B.; Krause, U.; Van Der Smissen, P.; Veithen, A.; Courtoy, P. J. (2000). "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. doi:10.1091/mbc.11.10.3453. PMC   15006 . PMID   11029048.
  7. ↑ Wang, J. T. H.; Kerr, M. C.; Karunaratne, S.; Jeanes, A.; Yap, A. S.; Teasdale, R. D. (2010). Caplan, Steve H. (ed.). "The SNX-PX-BAR Family in Macropinocytosis: The Regulation of Macropinosome Formation by SNX-PX-BAR Proteins". PLOS ONE. 5 (10): e13763. Bibcode:2010PLoSO...513763W. doi: 10.1371/journal.pone.0013763 . PMC   2966440 . PMID   21048941.
  8. ↑ Veithen, A.; Amyere, M.; Van Der Smissen, P.; Cupers, P.; Courtoy, P. J. (1998). "Regulation of macropinocytosis in v-Src-transformed fibroblasts: Cyclic AMP selectively promotes regurgitation of macropinosomes". Journal of Cell Science. 111 (16): 2329–2335. doi:10.1242/jcs.111.16.2329. PMID   9683628.
  9. ↑ Saeed, M. F.; Kolokoltsov, A. A.; Albrecht, T.; Davey, R. A. (2010). Basler, Christopher F. (ed.). "Cellular Entry of Ebola Virus Involves Uptake by a Macropinocytosis-Like Mechanism and Subsequent Trafficking through Early and Late Endosomes". PLOS Pathogens. 6 (9): e1001110. doi:10.1371/journal.ppat.1001110. PMC   2940741 . PMID   20862315.
  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. (2011). "Enterohemorrhagic Escherichia coli infection stimulates Shiga toxin 1 macropinocytosis and transcytosis across intestinal epithelial cells". AJP: Cell Physiology. 301 (5): C1140–C1149. doi:10.1152/ajpcell.00036.2011. PMC   3213915 . PMID   21832249.
  12. ↑ Valiya Veettil, M.; Sadagopan, S.; Kerur, N.; Chakraborty, S.; Chandran, B. (2010). Früh, Klaus (ed.). "Interaction of c-Cbl with Myosin IIA Regulates Bleb Associated Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus". PLOS Pathogens. 6 (12): e1001238. doi:10.1371/journal.ppat.1001238. PMC   3009604 . PMID   21203488.
  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.; Teasdale, R. D. (2010). "Inhibition of the PtdIns(5) kinase PIKfyve disrupts intracellular replication of Salmonella". The EMBO Journal. 29 (8): 1331–1347. doi:10.1038/emboj.2010.28. PMC   2868569 . PMID   20300065.
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