Why is nuclear envelope important

As a rate-limiting factor for cell migration, nuclear morphology and biomechanics are particularly important in the context of neutrophil migration during immune responses. Being an extremely plastic and fast migrating cell type, it is to be expected that neutrophils have an especially deformable nucleus. However, many questions still surround the dynamic capacities of the neutrophil nucleus, and which nuclear and cytoskeletal elements determine these dynamics.

Although past studies have investigated neutrophil nuclear composition and shape, in a new era of more sophisticated biomechanical and genetic techniques, 3D migration studies, and higher resolution microscopy we now have the ability to further investigate and understand neutrophil nuclear plasticity at an unprecedented level. This review addresses what is currently understood about neutrophil nuclear structure and its role in migration and the release of NETs, whilst highlighting open questions surrounding neutrophil nuclear dynamics.

The nucleus has long been considered the cell's control centre, housing genetic material and providing a biochemical factory for DNA replication and RNA synthesis. Being the largest organelle and up to ten times more rigid than the cytoplasm, the nucleus also exerts significant influence on cellular biomechanics 1 , 2. Albeit large, the nucleus is not a static organelle; rather it is itself capable of propagating intracellular forces 3 and dynamically changing its shape and integrity 4.

Biomechanical roles for the nucleus and its nuclear envelope have been identified during several cellular processes including cell division 5 , 6 , migration 3 , 7 , development, and tumourigenesis 4 , 8. However, gaps remain in our understanding of how nuclear plasticity specifically impacts cellular flexibility and motility—in particular, that of cancer cells, stem cells, and immune cells like neutrophils.

As the first leukocyte responders of the innate immune system, neutrophils exhibit a unique collection of migratory capabilities. These include high velocity, high deformability, and diverse forms of migration, such as transmigration and reverse migration 9 — Given that nuclei can transmit traction force through cells as they migrate 3 and nuclear deformability limits migratory speed 12 , it can be hypothesised that the nucleus is a key determinant of neutrophil migration. Additionally, neutrophils release neutrophil extracellular traps NETs The process of NET formation, often termed NETosis, requires chromatin release and extensive nuclear remodelling, yet it is a process that has not been well-characterised mechanically.

In light of new and emerging biological technologies, we are now in a position to examine the impact of nuclear dynamics on neutrophil function, including migration and NETosis. Neutrophils possess distinctive multi-lobulated nuclei and a particular nuclear envelope protein composition The functional capabilities of neutrophils that are impacted by their nuclear shape, composition and plasticity are fundamental to understanding their cellular biology. As an exhibitor of extreme nuclear plasticity, the neutrophil nucleus also sheds light on the broader nuclear biomechanics.

Neutrophils provide a unique cellular model for experimentally modulating a nucleus and demonstrating how specific nuclear components impact nuclear shape, and enhance flexibility and dynamics. This review firstly summarises nuclear biomechanics, and what is known about neutrophil nuclear structure and its influence on neutrophil maturation and migration. Secondly, it presents hypotheses for how the nucleus contributes to the unique plasticity and migratory ability of neutrophils.

Thirdly, the neutrophil nucleus is discussed in relation to NET release, and how nuclear mechanisms underpinning NETosis may lead to a greater understanding of this phenomenon. The nucleus, its nuclear envelope, and the surrounding cytoskeletal network contribute to and receive biomechanical forces that collectively determine nuclear morphology and location 3 , The interplay of these forces depends upon the cell type and its activity, with nuclear plasticity being the cumulative result of summed compressive, stretching, and shear stress forces.

However, a recent cell migration study demonstrated the important influence of 3-D environments on cellular and nuclear behaviour, with the nucleus an absolute requirement for 3D migration but not for migration in 1-D or 2-D contexts To determine nuclear dynamics during complex cell movements in complex 3-D environments, more sophisticated ex vivo and in vivo techniques are required, particularly if the aim is to elucidate how nuclear envelope components affect these dynamics.

The development of new mechanobiological methods 19 , animal models 20 , microfluidic devices 4 , 21 , and higher resolution imaging techniques 22 — 24 equip the field to answer such scientific questions. At the nuclear boundary, the nucleus is encased by the nuclear envelope, which protects and segregates chromatin and nucleoplasm from the cytoplasm.

The nuclear envelope is itself a stabilising and relatively rigid structure, and a key contributor to nuclear biomechanics. It consists of the double nuclear bilipid membrane, associated transmembrane proteins, and the nuclear lamina Figure 1A. Spanning the nuclear double membrane, the linker of nucleoskeleton and cytoskeleton LINC complex is formed by envelope proteins from the Nesprin and SUN protein families This LINC complex mediates nuclear-cytoskeletal coupling; the transmission of forces from the cytoplasm to nucleoplasm and vice versa The LINC complex also connects with chromatin, plectin, cytoplasmic cytoskeletal elements e.

Figure 1. Neutrophil nuclear envelope composition. A A typical nuclear envelope comprises of the nuclear membrane bilipid layer brown , which is embedded with membrane proteins like the LINC complex yellow and Lamin B Receptor orange , and with nuclear pore complexes blue.

External to the nuclear membrane, the nuclear envelope interacts with the cytoskeleton red. The lamina interacts with compact heterochromatin purple. For simplicity, many nuclear membrane proteins are not shown, and LaminB2 and LaminB1 are considered together.

Underlying the nuclear membrane is the nuclear lamina, a mesh-like structure comprised of lamin intermediate filaments 26 , Lamins are tethered to the nucleoplasmic interface of the inner nuclear membrane by integral envelope proteins Within the nucleoplasm, nuclear lamins interact with chromatin, anchoring it to the nuclear border at lamin-associated domains Direct and indirect connections between lamins and histone marks alter heterochromatin distribution, hence lamins likely affect epigenetic gene regulation 35 — The lamina is involved in nuclear-cytoskeletal coupling via its participation in the LINC complex, thus likely also plays a part in regulating mechanosensitive genes [reviewed in 40 ].

Nuclear lamins have highly conserved gene and protein structure 42 , 43 , and fall into two types: A or B. LaminA is the major A-type lamin. LaminC is identical in sequence to LaminA except for the exclusion of exon 10, which truncates the C-terminus by 30 residues A- and B-type lamins are not functionally redundant and interact with different protein partners Recent super-resolution microscopy revealed the lamina is a heterogeneous mesh, and the A- and B- type lamin networks show no clear overlap 22 , This arrangement of lamin filaments could represent functionally distinct microdomains, which may explain how different lamins regulate different chromatin regions, and interact uniquely with protein partners and complexes 22 , Further demonstrating their capacity to perform different functions, lamin mutations result in an array of diverse nuclear phenotypes affecting nuclear shape, integrity, size and chromatin arrangement [reviewed in 40 , 49 ].

Since the protein composition of the nuclear envelope differs across tissues and cell types 50 , there is scope for cell- and tissue-specific effects in both nuclear and cellular biomechanics.

Neutrophils are an amoeboid migratory cell type, possessing uniquely broad migratory capabilities encompassing cell speed, deformability, polarization, and directionality. This is in contrast to most other cells, which cannot pass through constrictions smaller than 1. Whilst the phenomenon of transmigration is well-documented and recently reviewed 10 , 57 , and the requirement for extreme nuclear deformability during transmigration is accepted in the literature, it has not been functionally defined.

Unlike mesenchymal cell migration, amoeboid neutrophils characteristically migrate in response to traction stresses and polarised signals from the rear of the cell rather than from the front This type of front-rear polarisation sees a contractile uropod at the cell rear and pseudopodia at the cell's leading edge. However, it is unlikely that the nucleus is merely subjected to this force, rather it is a force propagator that maintains the front-rear axis and helps neutrophils move forward faster and more effectively.

Using traction force microscopy in mesenchymal NIH 3T3 fibroblasts, nuclei have been shown to transmit intracellular traction forces across the cell anterior-posterior axis 3 , but similar studies have not been performed for migration of amoeboid leukocytes like neutrophils. Figure 2. Neutrophil nuclear dynamics during transmigration.

When undergoing transmigration through the endothelium brown neutrophils undergo extreme cellular and nuclear deformation. Different components of the cell and nucleus are believed to play roles in mechanically enabling this process, at the rear uropod, constriction point, and front of the cell toward the leading edge.

Some open questions in the field remain, but the consensus is that force generation and rear myosin-mediated contractility act to push the nucleus from behind, propelling the cell forward in concert with actin polymerisation at its leading edge. Characteristic of amoeboid-like cells, neutrophils often display multi-directional cytoplasmic extensions and movements.

Furthermore, neutrophil migration is unusual in the ability of cells to move in reverse without necessarily reversing their polarisation [ 11 , 61 reviewed by 10 , 57 ].

Reverse migration affords neutrophils the capability of not only rapidly migrating toward an immune challenge, but also of leaving it. Neutrophils can also return into the bloodstream from tissues by reverse transmigration across the endothelium. Before neutrophils undergo a change in direction, the centre of force generation in the cell rear has been shown to shift, most likely in preparation for the turn The nucleus may play a role in determining neutrophil directionality, via its influences on cellular mechanics and force transmission 3 , Interestingly, the nucleus in amoeboid leukocytes usually maintains a posterior-central position, but may translocate toward the cell's leading edge during migration due to constriction in the uropod [reviewed by 7 , 51 ].

As such, there could be an undescribed relationship between neutrophil nuclear position, the position of the force centre, and the ability of neutrophils to change direction.

The mature neutrophil nucleus displays a unique nuclear envelope protein profile. Specifically, there is a distinct pattern of LINC, lamins, and LBR relative expression, suggesting that the neutrophil-specific combination of these nuclear components has functional importance Figure 1B. As LaminB2 levels remain relatively constant, LaminB2 becomes the most highly expressed lamin in mature neutrophils Figure 3. This characteristic nuclear envelope composition is conserved across species and has been well-defined in in vitro studies of neutrophil-like HL cell differentiation, and ex vivo studies of mature peripheral human blood granulocytes and mouse granulocytes 63 , The development of mature neutrophil nuclei that are multi-lobulated is also widely conserved across species human, mouse and zebrafish 64 — 66 Figure 3.

The parallel conservation of both distinctive nuclear envelope composition and characteristic morphology strongly suggests a dual requirement of nuclear flexibility and shape for correct neutrophil function. Figure 3. Lamin and lamin B receptor expression in neutrophils related to neutrophil nuclear morphology. Changes in the expression of lamins and the lamin B receptor LBR during the transition from promyelocyte to mature neutrophil occurs in tandem with increasingly lobulated nuclear shape.

This multi-lobulated nuclear shape is conserved across species. Given its central role in nuclear structure and rigidity, the nuclear lamina network is predicted to make an important contribution to neutrophil cellular biomechanics. Table 1. Neutrophil nuclear components and their influence on nuclear form and function. Supporting this, softer nuclei have been shown to facilitate chromatin flow in the direction of nuclear movement DNA damage has been associated with chromatin stiffening in yeast 85 , hence the movement of chromatin material within the nucleus may become increasingly impacted as neutrophils sustain more DNA damage.

Interestingly, aged neutrophils migrate faster to inflammation sites 86 , potentially representing the mechanical effect of DNA damage whereby increased chromatin compaction increases deformability and mobility of the nucleus Additionally, as lamin expression is implicated in ageing 87 , regulation of lamins may play some part in this process.

Recent studies using microfluidic devices and nuclear localisation sequence-tagged fluorophores demonstrated that the nuclear envelope undergoes rupture and repair as fibroblasts, cancer cells, and dendritic neutrophils migrate, and that lamins are involved in this process 4 , Although not yet described in neutrophils, similar cycles of nuclear disruption and repair may occur as neutrophils migrate.

It is possible that as a highly migratory cell type, neutrophils have a more effective nuclear repair process to survive continual nuclear rupture. Alternatively, mature neutrophils may be ineffective at nuclear repair following repeated migration, and this could contribute to their short life span.

This suggests that increased composition of B-type lamins, specifically LaminB2, contributes to making neutrophil nuclei malleable, enhancing overall cellular plasticity. Regarding nuclear plasticity, B-type lamins have been somewhat neglected throughout the literature. A-type lamins have long been considered more important, as LMNA is clearly associated with many diseases, and is usually the lamin type predominantly expressed in terminally differentiated cells Nonetheless, LaminB1 and LaminB2 have distinct functions and have been linked to multiple effects on nuclear biomechanics, including nuclear shape, integrity and rigidity Studies investigating the role of B-type lamins in cell migration or cellular plasticity are scarce 89 , and are yet to be conducted specifically in neutrophils.

LMNB1 is also required for neuronal migration, with LaminB1 proposed to anchor the lamina such that chromatin remains sufficiently protected During sperm motility, LaminB1 was shown to dynamically redistribute—indicating a potential capacity for LaminB1 to influence migration via nuclear remodelling Via their interaction with LBR, B-type lamins may act to redistribute chromatin as cells migrate, however this has only been shown for LaminB1 during cell senescence in vitro There may also be an undetermined role for direct interactions between B-type lamins and heterochromatin Whilst LaminB2 is the major lamin in mature neutrophils, LaminB1 expression is down-regulated as neutrophils differentiate during granulocyte lineage progression 63 Figure 3.

When mouse bone marrow cells over-expressing LMNB1 were used for bone marrow transplantation, granulopoiesis led to fewer neutrophils, with larger, hyper-lobulated nuclei 68 Figure 3. This suggests LaminB1 expression influences the development, shape and function of the mature neutrophil nucleus. Reduced LaminB1 may also indicate the neutrophil nucleus is capable of greater rotation and movement within the cytoskeletal network 69 , and this increased nuclear mobility may facilitate cellular mobility.

Nuclear rotation is mediated by microtubules adjacent to the nuclear envelope, and microtubules have been shown to influence neutrophil polarity and migration using live imaging in zebrafish However, nuclear rotation in neutrophils has not yet been documented. In particular, actin networks and microtubules have been implicated in assisting nuclear constriction during migration, both in vitro 56 and in an in vivo C. Thiam et al. Perinuclear actin accumulation is also a process necessary for cancer cell nuclei to break and rupture during migration 96 , In HL cells, actin accumulation was more observable at the rear of neutrophils than at the nuclear border 56 , perhaps in keeping with the contractile uropod and posterior force generation used to squeeze neutrophils forward 58 , Class I myosins, unconventional myosins commonly involved with cortex actin dynamics, are likely also instrumental in pushing the nucleus during neutrophil migration.

Taken together, these data indicate a significant role for contractile myosins at the cell rear in neutrophil nuclear deformation Figure 2. Whilst perinuclear actin bundles appear dispensable during neutrophil migration, microtubules, another cytoskeletal element, may play crucial roles at the direct cytoskeleton-nucleus interface Figure 2. In migrating cells, microtubules are mostly nucleated at the centrosome or main microtubule organising centre MTOC , and radiate outwards around the nucleus.

In a similar study fixing PMNs during migration, MTOCs were shown to dynamically re-orient from the centre to the rear of the cell as neutrophils underwent polarisation However, neither of these two latter studies labelled or resolved nuclear lobe structure in relation to MTOC location. Live imaging of zebrafish neutrophils with labelled histone and tubulin showed MTOCs mainly localised in front of the nucleus, in contrast to previous in vitro studies Anterior rather than posterior positioning may be related to the stimuli type and strength involved in migration affecting the dynamics and localisation of the MTOCs This is supported by the Yoo et al.

Alternatively, the discrepancy could represent significant difference in MTOC-nucleus dynamics during 3D migration in vivo as opposed to 2D migration in vitro.

Variable MTOC positioning may also relate to the activation state and immune activity of neutrophils, given that changes in MTOC positioning corresponds to immune stimulation in other leukocytes such as cytotoxic T cells The prevalent concept of rear positioning of MTOCs in neutrophils undergoing polarized migration suggests a close microtubule-nuclear envelope interaction is needed, particularly at the location of force generation, to push the nucleus forward Figure 2.

Moreover, the close proximity of neutrophil MTOCs to their nuclei suggests that microtubules act on the non-resistive nuclear envelope, and contribute to the formation of the distinct nuclear lobes in neutrophils. Consistent with this, treatment of HLs with paclitaxel Taxol , a microtubule stabilising drug, resulted in induction of nuclear lobulation even in the absence of a neutrophil differentiation stimulus Conversely, treatment with the microtubule inhibitor nocodazole failed to generate nuclear lobes despite retinoic-acid induced differentiation Overall, it appears that cytoskeletal elements, particularly microtubules, do indeed play important roles in neutrophil nuclear deformability, positioning and lobulation.

However, the localisation and dynamism of cytoskeleton-nucleus interactions awaits more precise description. It is generally accepted that nuclear lobulation may assist neutrophil flexibility and migration, by generating less steric hindrance than round nuclei when neutrophils squeeze through the endothelium into tight tissue spaces.

Yet despite this being a long-standing view, limited supporting evidence exists. Neutrophil nuclear lobes have been shown to orientate to the rear of the cell in human neutrophils fixed and examined using transmission electron microscopy TEM and confocal microscopy , suggesting that nuclear lobes assume a preferential arrangement during neutrophil migration and directionality. A nuclear membrane is a double membrane that encloses the cell nucleus.

It serves to separate the chromosomes from the rest of the cell. The nuclear membrane includes an array of small holes or pores that permit the passage of certain materials, such as nucleic acids and proteins, between the nucleus and cytoplasm.

This notion is supported by the findings that repetitive NE ruptures induced by lack of a nuclear lamina 66 or during constricted migration can cause cell death Furthermore, constricted migration-induced NE rupture is associated with translocation of DNA repair factors from the nucleus to the cytosol as well as with DNA damage 58 , In this setting, damaged DNA cannot be properly repaired due to the mislocalization of repair factors from the nuclei.

In addition, caspase-independent, Bax-dependent NPR redistributes nuclear proteins 50 known to promote cell death, such as nucleophosmin 70 , 71 , 72 , Thus, SIGRUNB may amplify the apoptotic process, ensuring that cell death will be executed when initiated by activated Bax, but cannot occur because caspase activity is blocked.

This may occur with the expression of high amounts of inhibitors of apoptosis proteins. It is also known that cytosolic double-stranded DNA dsDNA binds to and directly activates the inflammasome-initiating sensors, AIM2, and this in turn induces the formation of the inflammasome, a caspase-1 activation platform Cytoskeletal forces are transmitted to the nucleus via the LINC complexes 20 , 79 , 80 , Non-apoptotic nuclear rupture may be caused by contractile forces imposed on the NE by actomyosin fibers via the LINC complex Furthermore, NE rupture in cancer cells with reduced lamin B1 expression depends on the assembly of contractile actin fibers and the LINC complex The cytoskeleton is subjected to reorganization during apoptosis This in turn may impose force transmitted by the LINC complex on the nucleus, which in combination with caspase-dependent or independent weakening of the nuclear lamina may cause GRUNB.

This effect may be mediated by coupling actin-myosin filaments to the LINC complex proteins nesprin-1 and nesprin-2 In addition, force exerted through focal adhesions causes nuclear deformations in a process mediated by stress fibers and LINC complexes. A similar effect may promote the early caspase-independent increase in NE leakiness observed during apoptosis 46 , To summarize, the apoptotic process via non-canonical action of Bax can cause local and transient alteration in the NE, which in turn leads to generation and subsequent rupture of nuclear bubbles.

This process, which might be mediated via the LINC complex, causes redistribution of nuclear proteins to the cytosol, which in turn may amplify the apoptotic process by several pathways. Emerin may act as an anti-survival protein by interfering with Notch signaling. This in turn impedes Notch-mediated survival signaling.

This assumption is supported by a study that showed that ER stress, a known apoptotic trigger 90 , clears emerin from the INM and ER, although by a different mechanism Knockdown of nesprin-1 93 or nesprin-2 94 can cause cell death. The mechanism whereby the different components of the LINC complex interact with the apoptotic machinery still need to be elucidated. The NE may serve as a platform to recruit apoptosis-promoting complexes.

In healthy cells of the nematode Caenorhabditis elegans , the pro-apoptotic protein, cell death gene CED -4, is neutralized by binding to the anti-apoptotic protein CED-9 in the mitochondria.

This translocation promotes the cell death process in a CEDindependent manner Moreover, CED-3 localizes to the perinuclear region in C. Assembly of apoptotic complexes in the NE may also occur in mammalian cells. Treatment of human cervical carcinoma C4-I cells with etoposide generates an NE-associated apoptotic promoting complex Intracellular membranes play a major role in apoptosis.

Of these, the mitochondrial outer membrane is the most studied, since its perforation plays an essential role in the Bcl-2 family-regulated intrinsic apoptotic pathway for a recent review see Kalkavan and Green However, the NE is also emerging as an important module of the death process, acting both as a target for destruction as well as a mediator Fig. Targeting the NE leads to a highly efficient and rapid manifestation of nuclear apoptosis.

The caspase-dependent destruction of the NPCs and the nuclear lamina perturb the NE barrier and its association with the chromatin. This in turn enables translocation of apoptotic factors to the nucleus, which then mediate its destruction. This process may occur at the late apoptotic stage following caspase activation and is associated with NE breakdown.

Apoptotic stress converges on the NE where it promotes two major effects. This in turn causes NE leakiness and entrance of caspases and nucleases from the cytosol to the nucleus, leading to NE breakdown and chromatin condensation and fragmentation. This nuclear destruction, along with additional non-nuclear events, culminate in apoptotic cell death. Some nuclear proteins such as nucleophosmin and histone 1.

Other nuclear proteins released to the cytosol may also contribute to cell death by yet unknown mechanisms. NE proteins can have pro- and anti-apoptotic effects and thus may regulate the apoptotic process. Furthermore, the NE can serve as a platform for the recruitment and assembly of apoptosis-promoting complexes. However, the NE is not only a target but can participate in mediating the apoptotic process. SIGRUNB and the associated NPR leads to translocation of several nuclear proteins from the nucleus to the cytosol, some of which can promote apoptosis via the mitochondrial pathway 50 , 70 , 71 , 72 , 73 , , This in turn may also contribute to cell death by accelerating apoptosis-induced DNA damage.

We hypothesize that SIGRUNB acts as an amplifier of the apoptotic process, which may be particularly relevant in cells in which caspase activity is constantly inhibited. The NE may also regulate apoptosis by the action of some of its proteins that can exert anti- or pro-apoptotic effects as well as by serving as a docking site for recruiting apoptosis-promoting complexes 95 , Via these mechanisms, the NE may therefore act as an amplifier of the apoptotic process.

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Ferrando-May, E. Nucleocytoplasmic transport in apoptosis. Falcieri, E. Small molecules, such as ions, can pass through the nucleus with ease. However, cargo proteins and RNAs that need to be transported require importins and exportins to enter and exit the nucleus, respectively. On one hand, the cargo binds with the importin in the cytoplasm, and then moved into the nucleus through the nuclear pore. On the other hand, the cargo binds with the exportin inside the nucleus, and then moved outside the nucleus via the nuclear pore.

Nuclear transport needs energy to proceed. Thus, GTPases e. Ran enzyme help by hydrolyzing GTP guanosine triphosphate so that energy would be released in the process. The energy released would be used to dissociate the cargo from the importins and to bind the cargo to the exportins.

The nuclear envelope compartmentalizes the nucleoplasm, setting boundaries between the nucleus and the cytoplasm. Nevertheless, it is perforated with holes called nuclear pores that regulate the exchange of substances for example, proteins and RNA between the nucleus and the cytoplasm. The nuclear transport of the large molecules like proteins and RNAs occurs via an active transport system carrier proteins while the passage of small molecules and ions occur passively via the nuclear pores.

Plant cells have plastids essential in photosynthesis. They also have an additional layer called cell wall on their cell exterior. Although animal cells lack these cell structures, both of them have nucleus, mitochondria, endoplasmic reticulum, etc.