An exception to this is the syntrophic consortium model, which envisages the simultaneous fusion of a symbiotic community composed of all three partners: cytoplasm, nucleus, and mitochondria [ 23 ],[ 24 ]. This holds that the nucleus evolved when a cell enclosed its sister after cell division, similar to the way in which endospores are formed in certain Gram-positive bacteria.
However, there is no evidence of endospore formation or other engulfment processes in Archaea, making this hypothesis improbable. Recent phylogenomic analyses have revealed that the eukaryotic genome likely represents a combination of two genomes, one archaeal [ 26 ],[ 27 ] and one proteobacterial [ 28 ],[ 29 ]. There is no evidence to support any additional, major genome donor as expected under nuclear endosymbiotic models [ 30 ].
Furthermore, endosymbiotic models including the endospore model require supplemental theories to explain the origin of the endomembrane system, the physical continuity of inner and outer nuclear membranes, and the formation of nuclear pores.
In light of these facts, we do not think that endosymbiosis provides a convincing explanation for the origin of the nuclear compartment [ 2 ],[ 7 ],[ 31 ]-[ 33 ]. Given the problems with endosymbiotic models, we believe that the most compelling current models for the origin of eukaryotes are those that invoke an autogenous origin of the nucleus. These usually suggest that a prokaryotic ancestor evolved the ability to invaginate membranes to generate internal membrane-bound compartments, which became organized around chromatin to generate a nucleus [ 32 ],[ 34 ]-[ 36 ].
In some models, infoldings of the plasma membrane were pinched off to form endoplasmic reticulum ER -like internal compartments that later became organized around the chromatin to form the inner and outer nuclear envelope [ 35 ],[ 37 ]-[ 39 ]. Alternatively, the nuclear membranes could be seen as arising from invaginations of the plasma membrane, so that the early eukaryote cell had an ER and nuclear envelope that were continuous with the outer cell membrane [ 40 ].
In either case, under these models the nuclear membrane is ultimately derived from internalized plasma membrane. Older autogenous outside-in models generally proposed that mitochondria were acquired by a cell that already had a nucleus [ 32 ],[ 34 ],[ 35 ] - in line with the results of early phylogenetic studies [ 41 ].
More recent phylogenetic data have suggested that mitochondria were present in the last eukaryotic common ancestor [ 42 ],[ 43 ]. This has led to the formulation of new autogenous models in which the acquisition of mitochondria predates the formation of the nuclear compartment [ 1 ],[ 23 ],[ 44 ]-[ 46 ]. Under the inside-out hypothesis, the outer nuclear membrane, plasma membrane, and cytoplasm were derived from extracellular protrusions blebs , whereas the ER represents the spaces between blebs Table 1.
Mitochondria were initially trapped in the ER, but later penetrated the ER membrane to enter the cytoplasm proper. Under the inside-out model, the final step in eukaryogenesis was the formation of a continuous plasma membrane, which closed off the ER from the exterior. Inside-out model for the evolution of eukaryotic cell organization. B We envision the eocyte cell forming protrusions, aided by protein-membrane interactions at the protrusion neck. These protrusions facilitated material exchange with proto-mitochondria.
C Selection for a greater area of contact between the symbionts would have led to bleb enlargement and the eventual loss of the S-layer from the protrusions. D Blebs would have then been further stabilized by the development of a symmetric nuclear pore outer ring complex Figure 2 and through the establishment of LINC complexes that, following the gradual loss of the S-layer, physically connected the original cell body the nascent nuclear compartment to the inner bleb membranes.
E With the expansion of blebs to enclose the proto-mitochondria, a process that would have facilitated the acquisition of bacterial lipid biosynthesis machinery by the host, the site of cell growth would have progressively shifted to the cytoplasm, facilitated by the development of regulated traffic through the nuclear pore.
At the same time, the spaces between blebs would have enabled the gradual maturation of proteins secreted into the environment via the perinuclear space through glycosylation and proteolytic cleavage.
F Finally, bleb fusion would have connected cytoplasmic compartments and driven the formation of an intact plasma membrane, perhaps through a process akin to phagocytosis whereby one bleb enveloped the whole.
This simple topological transition would have isolated the endoplasmic reticulum from the outside world, driven the full development of a system of vesicular trafficking, and established strict vertical transmission of mitochondria, leading to a cell with modern eukaryotic cell organization. Only one other paper that we are aware of has proposed that the nuclear compartment corresponds to boundaries of an ancestral cell. The exomembrane hypothesis of de Roos [ 47 ] is, however, quite distinct from the model put forward here.
De Roos postulated that the starting point was a proto-eukaryote with a double membrane that secreted membranous extracellular vesicles that fused to form an enclosing plasma membrane. Moreover, his model relies on an unconventional view of evolutionary history, including an independent origin of eukaryotic and prokaryotic cells.
Thus, we will not discuss the exomembrane hypothesis further. In the following sections, we describe the inside-out model in detail. We discuss the cellular processes involved in the generation of the cytoplasmic compartment, the vesicle trafficking system and plasma membrane, and cilia and flagella. In each section we point to relevant selective drivers and supporting evidence.
Finally, we look at some of the implications and testable predictions of the model and conclude by reflecting on the prospects for determining which of the models, inside-out or outside-in, is more likely to be correct.
We take as our starting point a prokaryotic cell similar to an 'eocyte' [ 48 ], an informal name that has come to refer to a member of the archaeal phyla Crenarchaeota, Thaumarchaeota, and Korarchaeota [ 49 ]. Eocytes usually have a single lipid bilayer membrane and a simple cell wall S-layer rich in N-glycosylated proteins [ 50 ]. They also have a relatively well-developed cytoskeleton that includes homologs of actin and tubulin [ 51 ]-[ 53 ] and the membrane-manipulating protein ESCRTIII [ 54 ]-[ 58 ].
While the inside-out hypothesis is not formally dependent on the veracity of the eocyte hypothesis, as we show below, the eocyte hypothesis poses a significant challenge to any outside-in hypothesis proposed to date. Under the inside-out model, the pre-eukaryote developed outward protrusions Figure 1 A,B. Many Archaea, including some eocytes [ 11 ],[ 13 ],[ 62 ], exhibit such structures [ 9 ]-[ 14 ],[ 62 ], but they are rarely seen in bacteria [ 54 ],[ 63 ].
In almost all cases where the images are clear, protrusions are bounded by an S-layer. However, if scission were suppressed, long-lived protrusions could be formed. The stable protrusions formed by suppression of scission would have increased the surface-to-volume ratio of the host cell. The idea that an eocyte might produce extracellular protrusions as a means to increase its surface area is justified by the observation that protrusion formation is stimulated in the crenarchaeote Stettaria hydrogenophila in response to reductions in the concentration of extracellular sulfur [ 9 ].
Moreover, Archaea with protrusions associated with cell-cell contacts have been seen in mixed microbial communities in biofilms [ 12 ]. The potential selective value of extracellular protrusions is also illustrated by a number of living eukaryotic groups, such as foraminiferans and radiolarians, which have a central cell body enclosed within a rigid test that has pores through which protrusions project.
This arrangement allows cells to interact directly and dynamically with the external environment while retaining their genetic material in a protective keep. These phyla are ecologically successful, with many thousands of living and extinct species [ 64 ]. The rapid radiation of foraminiferans in the Cambrian, not long after the evolution of rigid tests [ 65 ], makes clear the potential advantages of a cell increasing its surface area while retaining its chromatin in a protective inner compartment.
Further, it is noteworthy that in some rhizarian subgroups, pseudopodia fuse with one another to generate an extra-testal compartment that is loosely analogous to a continuous cytoplasm forming via the fusion of extracellular blebs. Little is currently known about the cell biology of archaeal protrusions. Specifically, it is unclear how protrusions are formed and stabilized. How cells generate stable protrusions is important for the model, since this corresponds to the first step in the evolution of the cytoplasm Figure 1.
COPII-like proteins do not associate with membranes directly, but interact with membranes via diverse membrane-binding proteins [ 67 ],[ 68 ]. Nonetheless, they play a conserved role in stabilizing positive membrane curvature [ 69 ], making them a natural candidate for having an ancestral role in stabilizing the bases of extracellular protrusions - a cellular location that corresponds to the nuclear pore of modern eukaryotes.
Example of epibiotic bacteria associated with archaeal cells. Model for the evolution of nuclear pores and cytoplasmic blebs. A Membrane protrusions are formed that extend through holes in the cell wall S-layer, shown in gray of the eukaryote ancestor. Protrusions could initially have been coated with an S-layer that was later lost.
Additionally, blebs may have been stabilized by an internal cytoskeleton red , like that provided by microtubules in modern day flagella, and by components of LINC complexes that connect the cell membrane and underlying structures to the S-layer gray. B Lateral spreading of the bleb is aided by the movement of LINC proteins to the inner bleb membrane and by the recruitment of a second, outer ring of nuclear pore proteins to stabilize positive curvature outside of the cell wall.
Under the inside-out model, the structural components of the nuclear pore constituted the very first eukaryotic innovation, playing an essential role in ensuring the stable attachment of extracellular protrusions to the cell body. This hypothesis leads one to expect the outer ring of the NPC to be the most highly conserved portion of the complex - as is the case [ 72 ]. Moreover, in line with the idea that the complex evolved to stabilize long-lived protrusions, NPCs are among the most stable proteins in eukaryotic cells [ 75 ],[ 76 ].
Within eukaryotes, there is now abundant evidence that structural components of the nuclear pore for example, Nup are homologous to COPII proteins that drive the budding of endomembrane vesicles [ 40 ],[ 68 ],[ 69 ],[ 72 ],[ 74 ],[ 77 ],[ 78 ]. This led Devos and collaborators to propose the protocoatomer hypothesis [ 40 ],[ 80 ], which assumes an outside-in origin of the nucleus.
They proposed that an ancestral protein involved in maintaining positive curvature around vesicles and at the edges of ER sheets underwent gene duplication, and some copies became specialized to function at nuclear pores - which are seen as being topologically equivalent to the edges of ER sheets. Under the inside-out model, this same homology is interpreted differently: proteins whose original function was to stabilize positive membrane curvature in the nuclear pore were later co-opted for a new function in vesicle formation.
To distinguish between these theories it will be important in future work to conduct a phylogenetic analysis of COPII and NPC proteins, rooted with appropriate prokaryotic sequences, to determine if the trees better support the inside-out or protocoatomer interpretation. We suggest that external protrusions evolved in the original proto-eukaryote to facilitate resource exchange with ectosymbiotic bacteria that ultimately gave rise to modern day mitochondria.
A number of modern bacteria form ectosymbiotic associations with specific hosts for examples, see [ 81 ]-[ 83 ] , including archaeal species. This illustrates the ecological plausibility of progenitors of mitochondria being ectosymbiotic bacteria that entered into a metabolic mutualism with the progenitor of the host cell. This type of association would be augmented by a progressive increase in host cell surface area.
Something similar is seen in the foraminiferan Bolivina pacifica , which increases its membrane surface area in parts of the cell that underlie prokaryotic ectosymbionts [ 85 ].
Thus, selection for an increase in the surface area available for metabolic exchange with ectosymbiotic bacteria could have driven production and proliferation of extracellular protrusions. The nature of the material exchange between the eukaryotic host and proto-mitochondria has been a matter of debate [ 23 ],[ 24 ],[ 44 ],[ 45 ]. Possibilities include hydrogen, sulfur, hydrogen sulfide, organic acids, and ATP. Nonetheless, the idea that efficient transfer between proto-mitochondria and a symbiotic archaeon selected for an increasing surface area of contact is shared by both the hydrogen and inside-out hypotheses.
Typically, analyses have identified mitochondria as very close relatives of Rickettsiales [ 87 ],[ 88 ], a group of intracellular parasites of eukaryotes that co-opt the host cell's phagocytic machinery to enter cells in food vacuoles, and then enter the cytoplasm proper by lysing the food vacuole membrane [ 87 ]. However, even if mitochondria are eventually confirmed as close relatives of Rickettsiales, for reasons discussed below we do not consider it likely that the ancestor of mitochondria entered its proto-eukaryotic host by phagocytosis.
Instead, we propose that mitochondria are derived from ectosymbionts, and that the endoparasitic capabilities of Rickettsiales evolved later. Material exchange with a mutualistic epibiotic bacterial community would have favored both loss of the S-layer overlying protrusions and lateral expansion of protrusions into larger blebs, increasing both cell volume and surface area Figure 1 B-D.
Such an expansion would have trapped populations of bacteria between the folds of adjacent blebs and the underlying cell wall Figure 1 C,D. This would have ensured sustained close contacts between host cytoplasm and proto-mitochondria, increasing the probability of vertical proto-mitochondrial inheritance, and helping to exclude parasitic microbes. At some point, either before or after further elaboration of the cytoplasmic compartment Figure 1 E,F , mitochondria moved into the cytoplasm by penetrating the ER membrane.
This seems plausible since rickettsialean bacteria, which are often found within the ER and Golgi of modern eukaryotes [ 89 ], gain entry to the cytoplasm proper by lysis of the confining host-cell membrane [ 87 ]. It is striking in this light that mitochondria in modern eukaryotes retain close metabolic, physical, and regulatory linkages with ER [ 90 ].
The ER has even been found to play a critical role in mitochondrial fission [ 91 ],[ 92 ]. The extent to which membrane protrusions swelled beyond the S-layer would have depended on the relative osmotic pressure of the cell and its environment, and the sophistication of osmoregulation.
While data on osmoregulation in Archaea remain sparse [ 93 ],[ 94 ], it is noteworthy that many archaeal cells live in conditions of high external osmolytes where the thinning or loss of the S-layer would not cause cells to burst. Thermoplasma , for example, appears to lack a cell wall entirely [ 95 ]. We propose that with the progressive growth of the external cytoplasmic compartment, adjacent blebs pressed against one another to generate a continuous network of inter-bleb crypts, homologous to the lumen of the nuclear envelope and the ER of modern eukaryotes Figure 1 D.
This would provide a simple explanation for the continuity of ER and the nuclear envelope, a common feature of all eukaryotes [ 96 ] even within the context of syncytia generated via incomplete cell division [ 97 ],[ 98 ]. Furthermore, since the location of the original glycoprotein-rich archaeal cell wall is topologically equivalent to the perinuclear space in modern eukaryotes, the model parsimoniously explains why the N-linked glycosylation pathway, which operates in the lumen of the nuclear envelope and ER to modify proteins destined for secretion, is homologous to that used to modify S-layer proteins in Archaea [ 99 ],[ ].
The stabilization of blebs would have been facilitated by the evolution of an outer ring of nucleoporins supporting a second area of positive curvature on the outside of the cell wall, giving rise to the partial inside-out symmetry of the NPC Figure 3. Additionally, the nucleus would have been stabilized by the co-option of proteins used to anchor the cell membrane to the inner surface of the S-layer. Under the model, these would have given rise to LINC complexes [ ],[ ].
In vertebrates, where nuclear envelope structure is best understood, the key components of LINC complexes are SUN-domain proteins on the nucleoplasmic side and KASH-domain proteins on the cytoplasmic side [ ]-[ ]. Torsin, which sits within the perinuclear space, interacts with SUN-KASH domain proteins [ ],[ ], as well as other linkers [ ],[ ].
These proteins function together to ensure the structural integrity of the nuclear envelope. Moreover, Torsin has been shown to play a role in nuclear bleb formation during ribonuclear protein granule export [ ],[ ] and in the control of ER morphology [ ].
Some of these functions are clearly ancient, given that SUN-domain proteins play a similar role in plant nuclei [ ],[ ]. Under the inside-out model, it seems likely that LINC complexes would be descended from archaeal S-layer glycoproteins.
We speculate further that LINCs originally functioned to connect the archaeal plasma membrane and perhaps cytoskeleton to the S-layer. Later, following the growth of cytoplasmic blebs, it is easy to imagine how gene duplication and the recruitment of new proteins could have connected the inner membranes of each bleb to remnants of the S-layer to create a perinuclear lumen and a double nuclear envelope.
Although this scenario is attractive, most of the what we know about the structure of the nuclear envelope comes from animal systems, and the identity of potential homologs in archaea remains unknown.
By contrast, SUN-domain protein are found in all eukaryotic groups and have structural homology to carbohydrate-binding motifs [ 72 ], which are also present in some archaeal proteins. Thus, it will be important to characterize the closest archaeal homologs of these nuclear envelope scaffolding proteins to determine whether they play a role in anchoring the plasma membrane to the S-layer, as we predict.
The majority of the structural lipids within eukaryotic cell membranes are quite distinct from archaeal lipids [ ],[ ]. In fact, they bear many similarities to those found in bacteria [ ]. Bacterial and eukaryotic membranes are primarily composed of ester-linked, straight-chain fatty acids and utilize glycerolphosphate lipids, whereas archaea have ether-linked fatty acids derived from highly methyl-branched isoprenoids and utilize a glycerolphosphate backbone [ ].
Additionally, both eukaryotes and some bacteria, but not archaea [ ], produce triterpenoids for example, hopanoids and sterols that help modulate membrane fluidity. This strongly suggests that eukaryotes acquired their bacterium-like lipids from mitochondria.
This conclusion is reinforced under the eocyte hypothesis, which embeds the eukaryotes within the Archaea, implying a late and dramatic switch from archaeal to bacterial lipid biochemistry. It seems likely that the transfer of genes for lipid biosynthesis from proto-mitochondria to proto-eukaryotes occurred prior to the development of an elaborate vesicle trafficking system and phagocytosis.
If this were not the case, one would have to postulate that numerous proteins that had evolved to manipulate archaeal membranes tolerated the shift towards bacterial membranes, which have distinct chemical and biophysical properties [ ],[ ].
While one can envisage a few membrane-interacting proteins, especially those with simple modes of interaction as seems to be the case for ESCRTIII [ ] , being able to retain functionality during a transition from archaeal to bacterial membranes, we think it likely that most membrane-manipulating machinery of eukaryotes arose after membranes were bacterium-like.
Furthermore, it is hard to see how processes like phagocytosis, which rely both on a large cell size and dramatic, energy-intensive membrane remodeling events could have occurred in an archaeal proto-eukaryote lacking mitochondria [ 1 ]. The contention that phagocytosis evolved after the acquisition of mitochondria as previously suggested [ 8 ] can be further justified by consideration of the physical properties of archaeal lipids.
Archaeal membranes typically retain their physical properties across a wide range of temperatures, whereas bacterial and eukaryotic membranes are tuned to keep them close to the phase transition boundary at physiological temperatures [ ]. The latter property is thought to allow the formation and dissolution of distinct lipid domains, which permits the dynamic and reversible membrane deformations that are characteristic of eukaryotic cells [ ].
These considerations support the idea that the physico-chemical properties of bacterial membranes were an essential precursor to the evolution of dynamic mechanisms such as endocytosis and phagocytosis. These facts are hard to reconcile with outside-in models, which typically view phagocytosis as the means by which proto-eukaryotes established a close, symbiotic relationship with proto-mitochondria. By contrast, the inside-out model implies that symbiosis arose by the passive trapping of proto-mitochondria in inter-bleb spaces, and did not require complex membrane manipulating machinery besides the ability to generate protrusions - a feature common in many modern-day archaea.
Under the inside-out model, the structural lipids present in modern eukaryotes would have been first acquired from mitochondria via traffic across ER-mitochondrial contact sites, which are conserved across eukaryotes and apparently ancient [ ]. Given this, there are a number of striking observations. First, mitochondria retain a critical role in eukaryotic fatty acid metabolism and in lipid synthesis, generating many of their own lipids, such as cardiolipin [ ],[ ].
Second, the ER is the major site of lipid and membrane synthesis in modern eukaryotes, with many of the enzymes involved found concentrated at ER-mitochondrial contact sites [ ]. And third, connections between ER and mitochondria remain important sites of lipid traffic in modern eukaryotes [ ]-[ ]. Thus, the spatial organization of lipids and lipid synthesis in modern cells is easy to understand under the inside-out model as a by-product of the gradual evolution of a symbiotic relationship between the host and mitochondria the original site of endomembrane lipid synthesis situated in the spaces between cytoplasmic blebs.
For a time it is likely that membranes were formed that contained a mixture of archaeal and bacterial lipids [ ] prior to gradual reductions in the archaeal contribution.
The primary use of only one type of structural lipid may have been driven in part by the difficulties of reconciling metabolic pathways that use different chiral forms of the lipid glycerol backbone, with the mesophilic environment removing any intrinsic benefit of ether-linked lipids. Interestingly, though, modern eukaryotic cells do produce some lipids with ether-linkages [ ],[ ], some of which have been implicated in the generation of mechanically rigid membranes during cell division [ ].
These facts raise the possibility that use of archaeon-like lipids in cell division helped ESCRTIII to survive the transition from archaeal to eukaryotic cell biology. In contrast to the structural lipids of eukaryotes, inositol lipids, which are ubiquitous in eukaryotes but represent a tiny fraction of total lipids in membranes [ ], are common to eukaryotes and archaea, but not bacteria [ ].
This implies that inositol metabolism was originally associated with the proto-nuclear compartment, thus explaining why inositol lipids are actively imported into mitochondria rather than being synthesized there [ ],[ ].
This may also account for the fact that inositol lipids, and the enzymes that generate them, are found in the nuclei of modern eukaryotes - something that has long perplexed researchers in the field [ ],[ ]. Instead of a structural role, inositol lipids are important regulatory molecules, modulating cell growth [ ],[ ] and marking cytoplasmic compartment identity [ ]. This is reasonable under the inside-out model: inositol derivatives were present throughout eukaryotic evolution, allowing their phosphorylation states to be deployed as signals [ ],[ ] for facilitating nuclear control over an increasingly large and elaborate cytoplasmic compartment.
Despite the presence of blebs and proto-mitochondria at early stages in its evolution Figure 1 A-D , the proto-eukaryote would have had the same topology as the ancestral eocyte.
It retained a single, continuous bounding membrane, albeit one that was much more extensive and contorted than the ancestors'. Thus, at this stage there would have been no distinction between nuclear division and cell division. Moreover, cell cycle progression and cell division would have likely been regulated in a manner similar to that seen in modern day Archaea, and using homologous proteins [ 58 ].
Likewise, proteins controlling chromosomal architecture histones and DNA replication are of archaeal origin [ ]. Strikingly, in many archaea, the scission event completing cell division is driven by the action of the ESCRTIII complex [ 56 ]-[ 58 ], just as appears to be the case in eukaryotes [ ]. Under the inside-out model, it is relatively easy to see how cell division could have been achieved in an early proto-eukaryotic cell, even one that had links between blebs, using pre-existing ESCRTIII machinery Figure 4.
After division, each daughter cell would have acquired a subset of the nuclear pore-associated blebs, with naked cell surface being covered by the movement of pores and through the action of LINC complexes [ ], which would attach flanking bleb membranes to the exposed portion of the proto-nucleus Figure 4. However, in a proto-eukaryote with a well-developed cytoplasmic compartment, the simple division of the nuclear compartment would not have guaranteed a fair segregation of cell mass between the two daughter cells.
After loss of the original cell wall, this problem could have been solved through the evolution of partially open mitosis Figure 4. Because the inner nuclear membrane is topologically continuous with the outer bleb membrane, this would have required little additional innovation, only the partial disassembly of nuclear pores and LINC complexes as seen in some eukaryotic cell divisions [ ].
Following division, the nuclear-cytoplasmic boundary would have been re-established through the rebinding of nuclear membranes by chromosome-associated NPC and LINC components. Model for the evolution of cell division. Cell division is depicted for the ancestral eocyte A , and at two intermediate stages in the evolution of eukaryotes, before B or after C bleb fusion.
Following the acquisition of blebs, ESCRTIII is used to drive the scission of cytoplasmic bridges connecting cells likely aided by the archaeal-derived actin cytoskeleton [ 51 ] , while LINC complexes and the formation of new nuclear pores restore cell and nuclear organization following division. Mitochondrial segregation is likely aided by host induced Dynamin-mediated scission within the endoplasmic reticulum not depicted , as observed in modern eukaryotes [ 91 ].
Instead, there is a loss of compartment identity as nuclear and cytoplasmic compartments mix and nuclear membranes become indistinguishable from cytoplasmic ER [ ]-[ ]. Under the inside-out model it is easy to see that open and closed mitosis are not as different as often assumed, and to imagine cells switching between open and closed modes of mitosis by modifying the extent to which LINC and NPCs remain associated with the nuclear membranes during cell division.
This offers an explanation for the frequent occurrence of evolutionary transitions between these two modes of mitosis [ 2 ],[ ]. Under the inside-out model, the recruitment of additional proteins to the NPC enabled the controlled movement of membrane lipids and the flow of aqueous material between the nuclear and bleb cytoplasmic compartments.
This includes the regulated transport of mRNA and ribosomes [ ],[ ] to generate distinct domains of protein translation: nuclear and cytoplasmic.
In such a situation, it is easy to imagine that it might be beneficial for certain transcripts to be translated in the cytoplasmic domain and that this might have resulted in the evolution of mechanisms for targeting some transcripts for transport to the cytoplasm and for preventing their premature translation in the nucleus. We speculate that mRNA cap formation and polyadenylation evolved originally for this purpose: tagging certain transcripts for translocation through the nuclear pore and limiting intranuclear translation.
It is noteworthy that, in some systems, mRNA processing [ ],[ ] and mRNA export [ ] are regulated by phosphoinositol lipids which, as suggested above, might have had an ancestral role in coordinating growth of the nuclear and cytoplasmic compartments. Through the regulated transport of mRNA and proteins between nuclear and cytoplasmic compartments it would have become possible to separate core metabolic processes in the cytoplasm from DNA replication, transcription, and ribosome assembly in the nucleoplasm.
This would have limited the exposure of the genome to the dangerous by-products of metabolism for example, reactive oxygen species generated in mitochondria. In addition, the separation of transcription, RNA processing, and translation provided more control over gene expression, making possible, for example, the evolution of alternative splicing [ ]. In the ancestral eocyte, signal recognition particle SRP complexes would have driven the secretion of proteins through the plasma membrane into the environment.
From this starting point, we propose that some SRP complexes, which are apparently of archaeal rather than mitochondrial origin [ ], became concentrated on bleb membranes close to the original cell body. This caused ribosome-mediated protein export to be directed into the perinuclear lumen and the proximal ER; thereby generating rough ER.
This altered plumbing would have limited the exposure of newly secreted proteins to the environment, and would have generated an extracellular pool of highly concentrated protein that could be subjected to complex modifications prior to its diffusion beyond the cell. While there are few cases of N-linked glycosylation in bacteria, archaea have an N-linked protein glycosylation pathway that has many similarities to that seen in eukaryotes, and which operates to modify secreted and transmembrane proteins [ 99 ],[ ].
The glycosyltransferases that add sugar groups to asparagine residues on secreted archaeal proteins are closely related to the equivalent eukaryotic enzymes [ ]. These data support the idea that the machinery governing eukaryotic protein glycosylation was inherited from archaea - where N-glycosylation appears to contribute to the structural integrity of the S-layer [ 50 ].
Under the inside-out model, the glycosylation machinery would have been situated in the extracellular space at the base of cytoplasmic blebs early in the evolution of eukaryotes - equivalent to the lumen of the nuclear envelope and ER of modern eukaryotes see Figure 1. Thus, the model provides a simple explanation for the origin of the machinery governing protein glycosylation, the site of glycosylation with eukaryotic cells, and its function in secretion. The increase in the relative size of the cytoplasmic compartment would have been aided by the evolution of an increasingly sophisticated cytoplasmic cytoskeleton and by the thinning or loss of residual cell wall material Figure 1 C.
Moreover, because it would have occurred through the expansion of cytoplasmic blebs, this increase in mass could have been achieved without a large change in surface-to-volume ratio. At the same time, the growth of individual cytoplasmic compartments would have necessitated the evolution of machinery to generate connections between adjacent blebs in order to integrate processes across these increasing large cells for example, facilitating accurate cell division and cell polarization.
While topologically equivalent endomembrane fusion events have not, to our knowledge, been studied in modern eukaryotes, the presence of fenestrae in Golgi [ ] and ER [ ] suggests the likely operation of such mechanisms.
Moreover, the topological transformation required to link cytoplasmic compartments is identical to the one proposed to function during the insertion of nuclear pores into interphase nuclei see below.
Thus, it is possible that proteins generating ER fenestrae and bleb-to-bleb connections are related to Ndc1, POM, and Gp, which are thought to facilitate the fusion of the inner and outer nuclear membranes during nuclear pore insertion [ ].
This type of fusion activity is also likely to have been a pre-requisite for the evolution of sex in eukaryotes. The final topological innovation under the inside-out model was the formation of a single, continuous plasma membrane.
Eukaryotic cells containing mitochondria then engulfed photosynthetic bacteria, which evolved to become specialized chloroplast organelles. In addition to double membranes, mitochondria and chloroplasts also retain small genomes with some resemblance to those found in modern prokaryotes.
This finding provides yet additional evidence that these organelles probably originated as self-sufficient single-celled organisms. Today, mitochondria are found in fungi, plants, and animals, and they use oxygen to produce energy in the form of ATP molecules, which cells then employ to drive many processes.
Scientists believe that mitochondria evolved from aerobic , or oxygen-consuming, prokaryotes. In comparison, chloroplasts are found in plant cells and some algae, and they convert solar energy into energy-storing sugars such as glucose. Chloroplasts also produce oxygen, which makes them necessary for all life as we know it. Scientists think chloroplasts evolved from photosynthetic prokaryotes similar to modern-day cyanobacteria Figure 4.
Today, we classify prokaryotes and eukaryotes based on differences in their cellular contents Figure 5. Figure 5: Typical prokaryotic left and eukaryotic right cells In prokaryotes, the DNA chromosome is in contact with the cellular cytoplasm and is not in a housed membrane-bound nucleus.
In eukaryotes, however, the DNA takes the form of compact chromosomes separated from the rest of the cell by a nuclear membrane also called a nuclear envelope. Eukaryotic cells also contain a variety of structures and organelles not present in prokaryotic cells. Throughout the course of evolution, organelles such as mitochondria and chloroplasts a form of plastid may have arisen from engulfed prokaryotes. A paradigm gets shifty. Nature , All rights reserved.
Mitochondria — often called the powerhouses of the cell — enable eukaryotes to make more efficient use of food sources than their prokaryotic counterparts. That's because these organelles greatly expand the amount of membrane used for energy-generating electron transport chains. In addition, mitochondria use a process called oxidative metabolism to convert food into energy, and oxidative metabolism yields more energy per food molecule than non-oxygen-using, or anaerobic , methods.
Energywise, cells with mitochondria can therefore afford to be bigger than cells without mitochondria. Within eukaryotic cells, mitochondria function somewhat like batteries, because they convert energy from one form to another: food nutrients to ATP.
Accordingly, cells with high metabolic needs can meet their higher energy demands by increasing the number of mitochondria they contain. For example, muscle cells in people who exercise regularly possess more mitochondria than muscle cells in sedentary people.
Prokaryotes, on the other hand, don't have mitochondria for energy production, so they must rely on their immediate environment to obtain usable energy. Prokaryotes generally use electron transport chains in their plasma membranes to provide much of their energy. The actual energy donors and acceptors for these electron transport chains are quite variable, reflecting the diverse range of habitats where prokaryotes live.
In aerobic prokaryotes, electrons are transferred to oxygen, much as in the mitochondria. The challenges associated with energy generation limit the size of prokaryotes. As these cells grow larger in volume, their energy needs increase proportionally. However, as they increase in size, their surface area — and thus their ability to both take in nutrients and transport electrons — does not increase to the same degree as their volume.
As a result, prokaryotic cells tend to be small so that they can effectively manage the balancing act between energy supply and demand Figure 6. Figure 6: The relationship between the radius, surface area, and volume of a cell Note that as the radius of a cell increases from 1x to 3x left , the surface area increases from 1x to 9x, and the volume increases from 1x to 27x. This page appears in the following eBook. Aa Aa Aa. Eukaryotic Cells. Figure 1: A mitochondrion.
Figure 2: A chloroplast. What Defines an Organelle? Why Is the Nucleus So Important? Why Are Mitochondria and Chloroplasts Special? Figure 4: The origin of mitochondria and chloroplasts. Mitochondria and chloroplasts likely evolved from engulfed bacteria that once lived as independent organisms. Figure 5: Typical prokaryotic left and eukaryotic right cells. The best guesses for the time when eukaryotes evolved range from just below 2. Work by Gonzalo Vidal of the University of Uppsala in Sweden indicates that single-celled planktonic eukaryotes certainly date back to 1.
The early fossil record is very sparse, however, and small eukaryotic cells present in the fossil record would not necessarily have been positively identified. My colleagues generally agree that the fossil record provides only a most recent estimate for the time when eukaryotes were already abundant; they might have been around a long time before they made it into the fossil record in a recognizable form.
Although that approach has been successfully used to decipher relations between organisms, calibrating it to measure the time elapsed since the divergence of phylogenetic branches is problematic; concerning the early evolution of life, there is no generally accepted approach. Most attempts to date early molecular phylogenetic trees used the emergence of eukaryotes around 2.
Russell F. Doolittle and his co-workers at the University of California at San Diego recently attempted to extend the calibration further into the past, but this work is contested. The controversy centers on possible cases of horizontal gene transfer across phylogenetic branches that were ignored by these authors and on an insufficient correction for multiple substitutions.
In addition, these backward extrapolations assume that the rate of molecular change at the time the eukaryotes originated is the same as it was during the metazoan evolution, when in fact it was probably much faster. Three prokaryotic components can be traced by comparing molecules in extant prokaryotes and eukaryotes. These components are the mitochondria derived from purple bacteria , the plastids from cyanobacteria , and the nucleocytoplasmic component from archaebacteria.
Other features in eukaryotic cells--for instance, the cytoskeleton--may also be of bacterial descent, but so far the molecular record has not yielded unambiguous clues as to their origin. There is an active dispute as to whether some of the archaebacteria are more closely related to the eukaryotic nucleocytoplasm than are others proponents of the differing views are James Lake of the University of California at Los Angeles and Carl Woese of the University of Illinois at Urbana-Champaign.
Regardless of how the debate is resolved, the ancestor of the eukaryotic nucleocytoplasm must have separated from the archaebacteria early in, or even before, the era when the major archaebacterial groups arose.
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