title: A mechanical bottleneck explains the variation in cup growth during FcgammaR phagocytosis.
abstract: Phagocytosis is the process by which cells internalize particulate material, and is of central importance to immunity, homeostasis and development. Here, we study the internalization of immunoglobulin G-coated particles in cells transfected with Fcgamma receptors (FcgammaRs) through the formation of an enveloping phagocytic cup. Using confocal microscopy, we precisely track the location of fluorescently tagged FcgammaRs during cup growth. Surprisingly, we found that phagocytic cups growing around identical spherical particles showed great variability even within a single cell and exhibited two eventual fates: a cup either stalled before forming a half-cup or it proceeded until the particle was fully enveloped. We explain these observations in terms of a mechanical bottleneck using a simple mathematical model of the overall process of cup growth. The model predicts that reducing F-actin concentration levels, and hence the deforming force, does not necessarily lead to stalled cups, a prediction we verify experimentally. Our analysis gives a coherent explanation for the importance of geometry in phagocytic uptake and provides a unifying framework for integrating the key processes, both biochemical and mechanical, occurring during cup growth.
authors.affiliation: Centre for Integrative Systems Biology Imperial College (CISBIC), South Kensington Campus, Imperial College London, London, UK.
authors.forename: Jeroen S
authors.initials: JS
authors.lastname: van Zon
authors.forename: George
authors.initials: G
authors.lastname: Tzircotis
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Caron
authors.forename: Martin
authors.initials: M
authors.lastname: Howard
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004058:Diffusion; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D008962:Models, Theoretical; D010587:Phagocytosis; D017452:Receptors, IgG / Q000737:chemistry*; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods
chemical_list: D000199:Actins; D017452:Receptors, IgG; D049452:Green Fluorescent Proteins
references.citation: J Leukoc Biol. 2004 Dec;76(6):1093-103
references.pmid: 15466916
references.citation: Science. 1991 Dec 20;254(5039):1785-8
references.pmid: 1837175
references.citation: Nat Rev Immunol. 2008 Feb;8(2):131-41
references.pmid: 18219310
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11691-6
references.pmid: 9751727
references.citation: Nature. 1991 May 9;351(6322):155-8
references.pmid: 1903183
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9469-74
references.pmid: 15972807
references.citation: J Cell Sci. 1992 Apr;101 ( Pt 4):907-13
references.pmid: 1527185
references.citation: Nat Rev Mol Cell Biol. 2008 Aug;9(8):639-49
references.pmid: 18612320
references.citation: J Biol Chem. 2006 Mar 31;281(13):8756-64
references.pmid: 16434390
references.citation: J Exp Med. 1998 Jan 19;187(2):161-76
references.pmid: 9432974
references.citation: J Cell Biol. 2001 Jan 8;152(1):165-80
references.pmid: 11149929
references.citation: J Cell Biol. 2000 May 1;149(3):697-706
references.pmid: 10791982
references.citation: J Cell Biol. 2004 Jan 19;164(2):185-94
references.pmid: 14718518
references.citation: J Cell Biol. 2003 Jun 23;161(6):1143-50
references.pmid: 12810696
references.citation: J Cell Sci. 1999 Dec;112 ( Pt 24):4705-13
references.pmid: 10574718
references.citation: Cell. 2005 Oct 7;123(1):157-70
references.pmid: 16213220
references.citation: J Cell Biol. 1974 Sep;62(3):647-59
references.pmid: 4368822
references.citation: Cell Mol Life Sci. 2008 Jul;65(13):1957-76
references.pmid: 18322649
references.citation: J Exp Med. 1974 Feb 1;139(2):323-36
references.pmid: 4149357
references.citation: Blood. 1994 Sep 15;84(6):1753-9
references.pmid: 7521687
references.citation: Nat Cell Biol. 2008 Aug;10(8):955-63
references.pmid: 18641640
references.citation: J Exp Med. 1975 Nov 1;142(5):1263-82
references.pmid: 1194852
references.citation: J Cell Sci. 2005 May 1;118(Pt 9):1789-97
references.pmid: 15827090
references.citation: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4930-4
references.pmid: 16549762
references.citation: Nature. 2007 Jan 4;445(7123):95-101
references.pmid: 17151602
references.citation: Biophys J. 1994 Aug;67(2):696-705
references.pmid: 7948682
references.citation: Science. 1998 Nov 27;282(5394):1717-21
references.pmid: 9831565
references.citation: Exp Cell Res. 1986 Feb;162(2):449-61
references.pmid: 3080317
references.citation: Ann Hematol. 1998 Jun;76(6):231-48
references.pmid: 9692811
references.citation: Semin Cell Dev Biol. 2004 Dec;15(6):679-89
references.pmid: 15561587
references.citation: Immunol Lett. 1988 Feb;17(2):159-68
references.pmid: 2452135
references.citation: J Exp Med. 1990 Dec 1;172(6):1853-6
references.pmid: 2124254
references.citation: Exp Cell Res. 1972 Aug;73(2):383-93
references.pmid: 5054338
references.citation: J Cell Sci. 2006 May 1;119(Pt 9):1903-13
references.pmid: 16636075