Clathrin Mediated Endocytosis and its Role in Viral Entry

Clathrin Mediated Endocytosis and its Role in Viral Entry


1Richard Tourdot, 2Ravi Radhakrishnan

1Department of Chemical Engineering and Materials Science, University of Minnesota 421 Washington Ave SE,
Minneapolis, Minnesota 55455, USA (RT);
2Department of Bioengineering, University of Pennsylvania, Philadelphia,
Pennsylvania 19104, United States (RR)


March 2013



Mechanisms for Viral Entry

Viruses can enter the cell in a variety of ways, either through direct membrane fusion/penetration reactions at the plasma membrane, or by undergoing endocytosis followed by a similar breaching of the cell membrane in an early endosome (Grove and Marsh, 2011). Viral entry begins after the virus has attached to the host cell through nonspecific glycoproteins tethers (Marsh and Helenius, 2006). The specific internalization pathway chosen by a virus depends on the characteristics of the virus, and the host cell type. The HIV virus enters the cell through membrane fusion at the plasma membrane, and can only infect cells that express the CD4 surface glycoprotein (Maddon et al., 1986), while the Hepatitis C virus requires a combination of specific glycoproteins to trigger its clathrin-mediated internalization and subsequent membrane fusion reactions in an early endosome (Blanchard et al., 2006). Viruses that hijack endocytosis and later are unlocked from an endosome do not have to contend with the cortical actin barrier present on the plasma membrane, and can rely on endosome specific environmental cues, such as low pH to initiate fusion/penetration reactions (Marsh and Helenius, 2006). The specific endocytosis pathway co-opted by the virus also depends on the virus size and shape, with larger viruses such as mimivirus requiring internalization through actin-dependent phagocytosis (Ghigo et al., 2008), and long tubule like viruses such as Ebola utilizing macropinocytosis (Saeed et al., 2010). The most common form of viral internalization is through clathrin-mediated endocytosis; this pathway internalizes Influenza A, vesicular stomatitis virus, and many others (Mercer et al., 2010).


Internalization through Endocytosis

Endocytosis is a cellular process by which a vesicle buds off from the cell membrane to be released into the cytosol. As the initial step in the shuttling events of vesicles from the plasma membrane and between endosomal compartments; this process modulates several essential cellular functions. Endocytic functions include the internalization of extracellular cargo, the regulation of receptor levels on plasma membrane, and the control of lipid composition of different intercellular compartments, and the plasma membrane; it also acts as a conduit for chemical neurotransmission, and other cell-cell communication (Schmidt, 2002; Oved and Yarden, 2002; Sorkin and von Zastrow, 2002). These vital transport roles of endocytosis, specifically transport from the plasma membrane, show its appreciation in a wide variety of cellular research including drug delivery, and viral entry. Several different forms of endocytosis are present in vivo including phagocytosis, macropinocytosis, caveoli mediated endocytosis, and clathrin mediated endocytosis (CME) (Doherty and McMahon, 2009). Phagocytosis is the engulfment of large extracellular particles above about a micron, and is used by macrophages to recognize, engulf and degrade bacteria (Flannagan et al., 2012). Macropinocytosis is similar to phagocytosis, but is non-specific in the cargo it carries and is used by cells to internalize large quantities of extraellular fluid and membrane (Lim and Gleeson, 2011). Caveoli-mediated endocytosis is an internalization process that originates from small inward lipid raft blebs on the order of 50 nm (Pelkmans and Helenius, 2002). CME involves the assembly of a coated plaque on the bilayer which induces a morphologically well defined budding vesicle on the order of 50 nm, and has been shown to internalize particles up to 200 nm (Rejman, 2004). CME constitutes a large proportion of endocytic events in vivo depending on cell type, and will be the focus of this review (Doherty and McMahon, 2009).


1. Clathrin Mediated Endocytosis (CME)

Clathrin-mediated endocytosis requires the assembly of a protein coat on the membrane in order to induce curvature and form a spherical invagination. Besides the scaffolding protein Clathrin some key factors implicated in CME include Epsin, Eps15, Ampiphisin, Adaptor Protein 2 (AP2), Dynamin, Actin, and the phospholipid Phosphatidylinositol 4,5-bisphosphate (PIP2) (Kirchhausen, 2000a; Czech, 2000). A detailed interaction map of the proteins, kinases, and lipids involved in CME can be found in the review by McMahon and Boucrot (McMahon and Boucrot, 2011). In the case of endocytic trafficking from the plasma membrane, these proteins co-localize and complex on the cytosolic side of the plasma membrane to form a coat at the site of endocytosis. The phospholipid PIP2, which makes up less than one percent of all lipids, has been shown to localize to endocytic sites in high concentrations, where it binds a variety of membrane proteins. Electron micrographs of these CME coats show well defined lattice clathrin plaques forming the backbone to the budding vesicle (Saffarian et al., 2009). The process of CME can be separated into several steps, which include: (1) the nucleation of a clathrin coated pit (CCP); (2) cargo capture in coated pits; (3) curvature induction and membrane invagination; and (4) vesicle scission and uncoating (Ramanan et al., 2011). The entire process of endocytosis takes place on the order of seconds in vivo (Ehrlich et al., 2004). While the blueprint of endocytosis has been discerned and the major factors identified; biophysical insight into the energetics of generating and sustaining high membrane curvature remains largely unknown.

1.1 Formation of Clathrin Coated-Pits (CCP)
The nucleation of clathrin coated pits has been found to require a protein complex consisting of FCHo1/2, Eps15, and intersectin-1 (Henne et al., 2010). The FCHo complex initiates coat assembly through Eps15 which recruits AP-2 to the membrane (Benmerah et al., 1998). The FCHo complex contains a curvature inducing F-BAR homodimer that is thought to sculpt the nascent CCP (Henne et al., 2010). Curvature induction in the lipid bilayer is modulated by PIP2. Since PIP2 anchors the clathrin coat to the membrane, its levels must be tightly controlled during endocytosis (Sun et al., 2007). Synaptojanin is a phosphoinostide phosphatase that converts PIP3 to PIP2 and PIP2 to PIP, and it is recruited to the membrane during endocytosis by endophillin to regulate PIP levels (Song and Zinsmaier, 2003). PIP2 coordinates with the ENTH and BAR domains of membrane proteins to induce curvature (Yoon et al., 2010; Lundmark and Carlsson, 2010). The role of curvature generation in a nascent coat and the curvature-mediated recruitment of Eps15 and Epsin to the coat are still unclear. Epsin is an ENTH-domain membrane protein that coordinates with the lipid PIP2 and inserts an amphipathic helix into the the bilayer, inducing curvature in the bilayer through a lipid area asymmetry. Similar to Eps15, Epsin has AP-2 binding domains which can bind multiple AP-2 molecules (Morgan et al., 2003). AP-2 is a versatile adapter protein, that along with AP180 assembles the clathrin lattice (Hao et al., 1999). Clathrin is a triskelion scaffolding protein that possesses three legs which can each bind to AP-2 and other clathrin molecules (Kirchhausen, 2000b). AP-2 recruits clathrin to the membrane, and once the clathrin concentration reaches a critical level, the clathrin triskelia can polymerize to form a basket like lattice on the membrane (Rappoport et al., 2006).

1.2 Cargo Capture
The formation of a clathrin lattice structure triggers a subsequent increase in the activity of Adaptin-Associated Kinase I (AAK1). AAK1 phosphorilates AP-2 causing a large conformational change exposing a high affinity binding site for PIP2 and a trans-membrane cargo-binding site (Collins et al., 2002). The cargo is then bound to AP-2 either directly through its cargo-binding domain, or indirectly through class-specific adapters. The cargo-AP-2 complex triggers the activation of PIPK1, which increases the local concentration of membrane PIP2, which in turn extends the clathrin coat if cargo is present (Ungewickell and Hinrichsen, 2007; Krauss et al., 2003). This feedback loop of activation of PIPK1 could explain the matching of CCP size to the size of cargo seen in vivo (McMahon, 2011). If no cargo is present the coated pit has been observed to be aborted at a critical coat size (Ehrlich et al., 2004). This checkpoint coat size is thought to be due to the bending rigidity of the membrane resisting further coat development without cargo present to stabilize the large membrane deformation.

Figure 1. Mechanism for Cargo Capture. 1) Once cargo binds to Receptors on the cell surface, AP-2 is recruited to the bound receptor through the FCHo/Intersectin complex. 2) Clathrin binds to binds to AP-2 through the α2 and β2 appendage binding domains. 3) AAK1 is recruited by clathrin, and proceeds to phosphorylate the µ2 subunit of AP-2. 4) This phosphorylation causes a structural rearrangement of AP-2 where the µ2 subunit swings out, revealing a trans-membrane cargo binding domain. Cargo association with AP-2 increases activity of PIP kinase Type I-gamma, which increases the local concentration of PIP2.

1.3 Clathrin Coat Growth and Curvature Induction
As more AP-2 is recruited to the growing coat by Epsin and subsequently activated by AAK1 during clathrin polymerization, the coat spreads radially along the membrane. Since clathrin association with AP-2 disrupts the binding sites of Eps15 and Epsin with AP-2, these membrane proteins are then pushed out to the periphery of the growing coat, alowing for more AP-2 recruitment near the edges of the coat. It is seen in vivo that coated pit growth and membrane invagination proceed in tandem in CME (Hinrichsen et al., 2006; Lundmark and Carlsson, 2010). The development of curvature is thought to be mediated by a combination of epsin, amphiphysins and the clathrin coat itself (Yoon et al., 2010; Yoshida et al., 2004; Rao et al., 2010). The initial curvature generation may be driven by the nucleating FCHo complex (Henne et al., 2010). As Epsin is recruited to the growing coat by Eps15 and higher levels of PIP2, it proceeds to induce stronger curvature in the membrane by inserting an N-terminal amphipathic helix into the bilayer. The growing clathrin coat scaffolds the curvature, and since clathrin triskelia posess an intrinsic pucker angle, they polymerize to form a curved basketlike structure. Since individual clathrin heavy chains interactions are on the order of thermal fluctuations, clathrin is thought to play a more curvature stabilizing role in endocytosis. As the budding vesicle begins to emerge from the membrane, a tubular neck region is formed; this region is left uncovered by the clathrin coat, but contains high amounts of PIP2. The membrane proteins amphiphysin and endophillin are attracted to the vesicle neck through their N-BAR curvature sensing domains (Ringstad et al., 1999).

1.4 Vesicle Scission and Uncoating
After being recruited to the highly curved neck of the budding vesicle, Ampiphysins proceed to recruit dynamin. Upon binding dynamin, ampiphysins further aggregate at the neck, while dynamin polymerizes in a GTP dependent process into a helical collar on the budding vesicles neck (Fournier et al., 2003; Roux et al., 2006). The process of vesicle scission from the plasma membrane could be due to a combination of the dynamin collar pinching the neck in concert with some line tension in the neck generated by high concentration of PIP2. Once free from the plasma membrane, the coated vesicle recruits Rab5 which disrupts AP-2 binding to PIP2 (Semerdjieva et al., 2008). Synaptojanin then converts PIP2 to PI(4)P, which in turn with auxillin and Hsc70 disassembles the clathrin coat (Massol et al., 2006). After uncoating the vesicle undergoes endosomal sorting or degradation depending on the adapter and accessory proteins present on the vesicles surface (Traub, 2009).

Figure 2. CME and Viral Entry. Key steps of viral entry through CME include the Formation of the Clathrin Coated Pit (CCP), curvature induction to envelop cargo, vesicle scission and uncoating, and viral escape through an early endosome.


2. Membrane Elasticity and Curvature Induction

While an unstressed cell membrane remains relatively flat on the length scale of 100 nm, during endocytosis the cell membrane must deform and accommodate a high degree of curvature. Recent research has shown that membrane interacting domains of several key endocytic proteins such as the ENTH domain Epsins and the BAR domain Amphiphysins can both induce curvature and localize along curvature gradients. Curvature induction by membrane proteins is governed by both amphipathic helix insertion and electrostatic scaffolding (McMahon and Gallop, 2005). The ENTH domain of epsin contains an N-terminal amphipathic helix that inserts into the cytoplasmic leaflet of the plasma membrane. This helix insertion creates an area asymmetry between the two lipid leaflets in the bilayer, and the membrane curves to lower its elastic energy. The BAR domain family of Ampiphysins and Endophillins induces curvature along its banana shape through electrostatic interactions with charged lipids. These proteins curvature induction mechanism has been studied in detail, with Epsin having been shown to tubulate liposomes in vitro, and molecular dynamics simulations explicitly showing curvature induction by BAR domains (Ford et al., 2002; Blood and Voth, 2006). The degree to which these curvature inducing proteins direct membrane budding during endocytosis is unknown.

2.1 Curvature Sensing and Protein Localization
The role of curvature sensing in endocytosis and other cell membrane remodeling processes is also not well known. A membrane elasticity argument would dictate the diffusion of curvature inducing proteins (CIP) to highly curved regions of the membrane in order to minimize bending energy. This localization of membrane proteins along curvature gradients may play a role in the localization of endocytic machinery along a budding vesicle. Some recent in vitro experiments have quantified CIP's curvature sensing abilities. By pulling tethers from giant unilammalar vesicles experimentalists have been able to track migration of fluorescence tagged Epsin along mean curvature gradients (Capraro et al., 2010). It is also thought that BAR domain membrane proteins can sense Gaussian curvature, as they must localize to the neck region of a constricting vesicle and recruit dynamin. This Gaussian curvature sensing ability may be due to the anisotropic curvature field which it induces (Ringstad et al., 1999).

2.2 Actin Polymerization and Tension During Endocytosis
The role of actin in endocytosis is only recently coming to light. Actin is known to polymerize at the site of the budding vesicle during endocytosis. Experiments which knockout actin have shown a decrease in endocytosis rates, causing some CME events to be deemed actin-mediated endocytosis. Actin recruitment is required for CME to proceed on the apical surfaces of polarized cells which are under tension (Boulant et al., 2011). It is not clear exactly how actin interacts with the budding vesicle, but it's thought to modulate membrane surface tension, and decrease the energy barrier for forming a bud. Actin assisted membrane remodeling is required in yeast endocytosis, with ~200 nm long tubules pulled by actin easing the membrane energetics of budding (Liu et al., 2006).


3. Virus Entry and CME (Summary)

Virus internalization by CME is so prevalent that fluorescence tagged viruses are used as one tool to study key factors of CME such as cargo size (Ehrlich et al., 2004). The interplay between a viruses route of entry, whether through CME or otherwise, and simple physical factors, such as size and shape, has been shown to be one major determinant in viral infection. Studies of different aspect ratios of the Vesicular Stomatitis Virus have pointed to a shift from solely clathrin-mediated endocytosis to an actin dependent endocytosis as the virus gets longer (Cureton et al., 2010). These findings point to Clathrin-Mediated Endocytosis being a refined internalization route though which cells mechanistically counteract membrane tension, and overcome the energy barrier for enveloping cargo of a specific length scale.

Common Abbreviations: CME- Clathrin Mediated Endocytosis; CCP- Clathrin-Coated Pits; CCV- Clathrin-Coated Vesicle; AP-2- Adaptor Protein 2; PIP2- Phosphatidylinositol 4,5-bisphosphate


The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain.
Maddon PJ, Dalgleish AG, McDougal JS, Clapham PR, Weiss RA, Axel R.
Cell. 1986 Nov 7;47(3):333-48.
PMID 3094962
AP-2/Eps15 interaction is required for receptor-mediated endocytosis.
Benmerah A, Lamaze C, Begue B, Schmid SL, Dautry-Varsat A, Cerf-Bensussan N.
J Cell Biol. 1998 Mar 9;140(5):1055-62.
PMID 9490719
AP180 and AP-2 interact directly in a complex that cooperatively assembles clathrin.
Hao W, Luo Z, Zheng L, Prasad K, Lafer EM.
J Biol Chem. 1999 Aug 6;274(32):22785-94.
PMID 10428863
Endophilin/SH3p4 is required for the transition from early to late stages in clathrin-mediated synaptic vesicle endocytosis.
Ringstad N, Gad H, Low P, Di Paolo G, Brodin L, Shupliakov O, De Camilli P.
Neuron. 1999 Sep;24(1):143-54.
PMID 10677033
PIP2 and PIP3: complex roles at the cell surface.
Czech MP.
Cell. 2000 Mar 17;100(6):603-6. (REVIEW)
PMID 10761925
Three ways to make a vesicle.
Kirchhausen T.
Nat Rev Mol Cell Biol. 2000a Dec;1(3):187-98. (REVIEW)
PMID 11252894
Kirchhausen T.
Annu Rev Biochem. 2000b;69:699-727. (REVIEW)
PMID 10966473
Molecular architecture and functional model of the endocytic AP2 complex.
Collins BM, McCoy AJ, Kent HM, Evans PR, Owen DJ.
Cell. 2002 May 17;109(4):523-35.
PMID 12086608
Curvature of clathrin-coated pits driven by epsin.
Ford MG, Mills IG, Peter BJ, Vallis Y, Praefcke GJ, Evans PR, McMahon HT.
Nature. 2002 Sep 26;419(6905):361-6.
PMID 12353027
Signal transduction: molecular ticket to enter cells.
Oved S, Yarden Y.
Nature. 2002 Mar 14;416(6877):133-6.
PMID 11894079
Membrane transport: the making of a vesicle.
Schmidt AA.
Nature. 2002 Sep 26;419(6905):347-9.
PMID 12353016
Signal transduction and endocytosis: close encounters of many kinds.
Sorkin A, Von Zastrow M.
Nat Rev Mol Cell Biol. 2002 Aug;3(8):600-14. (REVIEW)
PMID 12154371
Dynamin recruitment by clathrin coats: a physical step?
Fournier JB, Dommersnes PG, Galatola P.
C R Biol. 2003 May;326(5):467-76.
PMID 12886874
ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Igamma.
Krauss M, Kinuta M, Wenk MR, De Camilli P, Takei K, Haucke V.
J Cell Biol. 2003 Jul 7;162(1):113-24.
PMID 12847086
Endophilin and synaptojanin hook up to promote synaptic vesicle endocytosis.
Song W, Zinsmaier KE.
Neuron. 2003 Nov 13;40(4):665-7. (REVIEW)
PMID 14622570
Endocytosis by random initiation and stabilization of clathrin-coated pits.
Ehrlich M, Boll W, Van Oijen A, Hariharan R, Chandran K, Nibert ML, Kirchhausen T.
Cell. 2004 Sep 3;118(5):591-605.
PMID 15339664
Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis.
Rejman J, Oberle V, Zuhorn IS, Hoekstra D.
Biochem J. 2004 Jan 1;377(Pt 1):159-69.
PMID 14505488
The stimulatory action of amphiphysin on dynamin function is dependent on lipid bilayer curvature.
Yoshida Y, Kinuta M, Abe T, Liang S, Araki K, Cremona O, Di Paolo G, Moriyama Y, Yasuda T, De Camilli P, Takei K.
EMBO J. 2004 Sep 1;23(17):3483-91. Epub 2004 Aug 19.
PMID 15318165
Membrane curvature and mechanisms of dynamic cell membrane remodelling.
McMahon HT, Gallop JL.
Nature. 2005 Dec 1;438(7068):590-6. (REVIEW)
PMID 16319878
Hepatitis C virus entry depends on clathrin-mediated endocytosis.
Blanchard E, Belouzard S, Goueslain L, Wakita T, Dubuisson J, Wychowski C, Rouille Y.
J Virol. 2006 Jul;80(14):6964-72.
PMID 16809302
Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations.
Blood PD, Voth GA.
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15068-72. Epub 2006 Sep 28.
PMID 17008407
Bending a membrane: how clathrin affects budding.
Hinrichsen L, Meyerholz A, Groos S, Ungewickell EJ.
Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8715-20. Epub 2006 May 30.
PMID 16735469
Endocytic vesicle scission by lipid phase boundary forces.
Liu J, Kaksonen M, Drubin DG, Oster G.
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10277-82. Epub 2006 Jun 26.
PMID 16801551
Virus entry: open sesame.
Marsh M, Helenius A.
Cell. 2006 Feb 24;124(4):729-40. (REVIEW)
PMID 16497584
A burst of auxilin recruitment determines the onset of clathrin-coated vesicle uncoating.
Massol RH, Boll W, Griffin AM, Kirchhausen T.
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10265-70. Epub 2006 Jun 23.
PMID 16798879
Dynamics of clathrin and adaptor proteins during endocytosis.
Rappoport JZ, Kemal S, Benmerah A, Simon SM.
Am J Physiol Cell Physiol. 2006 Nov;291(5):C1072-81.
PMID 17035303
GTP-dependent twisting of dynamin implicates constriction and tension in membrane fission.
Roux A, Uyhazi K, Frost A, De Camilli P.
Nature. 2006 May 25;441(7092):528-31. Epub 2006 Apr 30.
PMID 16648839
PtdIns(4,5)P2 turnover is required for multiple stages during clathrin- and actin-dependent endocytic internalization.
Sun Y, Carroll S, Kaksonen M, Toshima JY, Drubin DG.
J Cell Biol. 2007 Apr 23;177(2):355-67.
PMID 17452534
Endocytosis: clathrin-mediated membrane budding.
Ungewickell EJ, Hinrichsen L.
Curr Opin Cell Biol. 2007 Aug;19(4):417-25. Epub 2007 Jul 13. (REVIEW)
PMID 17631994
Ameobal pathogen mimivirus infects macrophages through phagocytosis.
Ghigo E, Kartenbeck J, Lien P, Pelkmans L, Capo C, Mege JL, Raoult D.
PLoS Pathog. 2008 Jun 13;4(6):e1000087. doi: 10.1371/journal.ppat.1000087.
PMID 18551172
Coordinated regulation of AP2 uncoating from clathrin-coated vesicles by rab5 and hRME-6.
Semerdjieva S, Shortt B, Maxwell E, Singh S, Fonarev P, Hansen J, Schiavo G, Grant BD, Smythe E.
J Cell Biol. 2008 Nov 3;183(3):499-511. doi: 10.1083/jcb.200806016.
PMID 18981233
Mechanisms of endocytosis.
Doherty GJ, McMahon HT.
Annu Rev Biochem. 2009;78:857-902. doi: 10.1146/annurev.biochem.78.081307.110540. (REVIEW)
PMID 19317650
Distinct dynamics of endocytic clathrin-coated pits and coated plaques.
Saffarian S, Cocucci E, Kirchhausen T.
PLoS Biol. 2009 Sep;7(9):e1000191. doi: 10.1371/journal.pbio.1000191. Epub 2009 Sep 8.
PMID 19809571
Tickets to ride: selecting cargo for clathrin-regulated internalization.
Traub LM.
Nat Rev Mol Cell Biol. 2009 Sep;10(9):583-96. doi: 10.1038/nrm2751. (REVIEW)
PMID 19696796
The length of vesicular stomatitis virus particles dictates a need for actin assembly during clathrin-dependent endocytosis.
Cureton DK, Massol RH, Whelan SP, Kirchhausen T.
PLoS Pathog. 2010 Sep 30;6(9):e1001127. doi: 10.1371/journal.ppat.1001127.
PMID 20941355
FCHo proteins are nucleators of clathrin-mediated endocytosis.
Henne WM, Boucrot E, Meinecke M, Evergren E, Vallis Y, Mittal R, McMahon HT.
Science. 2010 Jun 4;328(5983):1281-4. doi: 10.1126/science.1188462. Epub 2010 May 6.
PMID 20448150
Driving membrane curvature in clathrin-dependent and clathrin-independent endocytosis.
Lundmark R, Carlsson SR.
Semin Cell Dev Biol. 2010 Jun;21(4):363-70. doi: 10.1016/j.semcdb.2009.11.014. Epub 2009 Dec 1. (REVIEW)
PMID 19931628
Virus entry by endocytosis.
Mercer J, Schelhaas M, Helenius A.
Annu Rev Biochem. 2010;79:803-33. doi: 10.1146/annurev-biochem-060208-104626. (REVIEW)
PMID 20196649
Molecular basis for SH3 domain regulation of F-BAR-mediated membrane deformation.
Rao Y, Ma Q, Vahedi-Faridi A, Sundborger A, Pechstein A, Puchkov D, Luo L, Shupliakov O, Saenger W, Haucke V.
Proc Natl Acad Sci U S A. 2010 May 4;107(18):8213-8. doi: 10.1073/pnas.1003478107. Epub 2010 Apr 19.
PMID 20404169
Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes.
Saeed MF, Kolokoltsov AA, Albrecht T, Davey RA.
PLoS Pathog. 2010 Sep 16;6(9):e1001110. doi: 10.1371/journal.ppat.1001110.
PMID 20862315
Molecular basis of the potent membrane-remodeling activity of the epsin 1 N-terminal homology domain.
Yoon Y, Tong J, Lee PJ, Albanese A, Bhardwaj N, Kallberg M, Digman MA, Lu H, Gratton E, Shin YK, Cho W.
J Biol Chem. 2010 Jan 1;285(1):531-40. doi: 10.1074/jbc.M109.068015. Epub 2009 Nov 1.
PMID 19880963
Actin dynamics counteract membrane tension during clathrin-mediated endocytosis.
Boulant S, Kural C, Zeeh JC, Ubelmann F, Kirchhausen T.
Nat Cell Biol. 2011 Aug 14;13(9):1124-31. doi: 10.1038/ncb2307.
PMID 21841790
The cell biology of receptor-mediated virus entry.
Grove J, Marsh M.
J Cell Biol. 2011 Dec 26;195(7):1071-82. doi: 10.1083/jcb.201108131. Epub 2011 Nov 28. (REVIEW)
PMID 22123832
Macropinocytosis: an endocytic pathway for internalising large gulps.
Lim JP, Gleeson PA.
Immunol Cell Biol. 2011 Nov;89(8):836-43. doi: 10.1038/icb.2011.20. Epub 2011 Mar 22. (REVIEW)
PMID 21423264
Molecular mechanism and physiological functions of clathrin-mediated endocytosis.
McMahon HT, Boucrot E.
Nat Rev Mol Cell Biol. 2011 Jul 22;12(8):517-33. doi: 10.1038/nrm3151. (REVIEW)
PMID 21779028
Systems biology and physical biology of clathrin-mediated endocytosis.
Ramanan V, Agrawal NJ, Liu J, Engles S, Toy R, Radhakrishnan R.
Integr Biol (Camb). 2011 Aug;3(8):803-15. doi: 10.1039/c1ib00036e. Epub 2011 Jul 26. (REVIEW)
PMID 21792431
The cell biology of phagocytosis.
Flannagan RS, Jaumouille V, Grinstein S.
Annu Rev Pathol. 2012;7:61-98. doi: 10.1146/annurev-pathol-011811-132445. Epub 2011 Sep 9. (REVIEW)
PMID 21910624
Written2013-03Richard Tourdot, Ravi Radhakrishnan
of Chemical Engineering, Materials Science, University of Minnesota 421 Washington Ave SE, Minneapolis, Minnesota 55455, USA (RT); Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States (RR)


This paper should be referenced as such :
Tourdot, R ; Radhakrishnan, R
Clathrin Mediated Endocytosis, its Role in Viral Entry
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):583-588.
Free journal version : [ pdf ]   [ DOI ]
On line version :