Where is ubiquitin found




















Many aspects of ubiquitin's structure aids in this durability. Ubiquitin contains a hydrophobic core. The main contributor to the ubiquitin stability is the vast amount of hydrogen-bonding interactions observed.

The whole structure of ubiquitin undergoes significant hydrogen bonding, aside from the COOH terminus [1]. At first, ubiquitin was believed to be a hormone involed in inducing the differentiation of lymphocytes and activating adenylate cyclase [2]. However, today, ubiquitin is primarily known for its role in intracellular ATP-dependent protein degradation.

This is accomplished through the process of several seperate reactions:. The first step of ubiquitin activation involves the formation of a ubiquitin-adenylate intermediate. This reaction requires an E1 ubiquitin-activating enzyme. The second step of ubiquitin activation transfers ubiquitin to the E1 active site cysteine residue and AMP is released.

This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group [1]. The activated ubiquitin in then transferred to a ubiquitin-conjugating enzyme, E2, through a trans-thiolesteration reaction. This is accomplished by E2 directly [1].

Some proteins may be selected for degradation through the use of protein E3. E3 binds and catalyzes the isopeptide bond between ubiquitin and the target protein.

Several activated ubiquitin may be added while still bound to E2 following the first ubiquitin addition [1]. Before degradation is complete, the system must ensure that the protein that has been ubiquitinylated is in fact damaged. Enzymes associated with proofreading will either inhibit or stimulate the ubiquitin-dependent process of protein degradation. If the target protein is found to not be damaged, deconjugation of ubiquitin from mono- or polyubiquitinylated proteins will result in order to inhibit any further degradation processes.

This reverse reaction is known as a "futile cycle" [3]. This is done through the actions of deubiquitinating thiol proteases which recognize the native conformation of ubiquitin and cleave the isopeptide bond located at the carboxyl-terminal Gly76 of ubiquitin [4]. If, however, the target protein is found to be damaged, the ubiquitinylated protein is lead to its degradation by the 26S proteasome [5].

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Although one of the major roles of the proteasome is to degrade oxidatively modified proteins, whether ubiquitination is required remains elusive Shang and Taylor, This is an interesting issue since there is ample evidence that neural tissues are especially vulnerable to oxidative stress, which is linked to AD pathogenesis Eckert et al.

Neurons exhibit a higher sensitivity to proteasome inhibition than astrocytes, mostly because they exhibit increased levels of oxidized proteins Dasuri et al. Interestingly, cysteine deubiquitinases are proposed to be highly sensitive redox biosensors that become inactive and promote a quick response independent of protein synthesis or protein modification Cotto-Rios et al. Furthermore, Klinked polyubiquitination was proposed to be a new modulator of the oxidative stress response induced by peroxides Silva et al.

Disrupting Klinked polyubiquitination under peroxide-induced oxidative stress destabilizes polysomes, impairs protein synthesis, and increases the vulnerability of cells to stress Silva et al.

Thus Klinked polyubiquitination seems to play a new role as a redox-regulator of protein translation by ribosomes, while Klinked polyubiquitination regulates protein degradation by proteasomes. Another deleterious mechanism associated with mitochondrial dysfunction is the limitation in ATP production that can cause an energy crisis in neurons Nicholls, Degradation of proteins by the 26S proteasome is highly dependent on ATP binding and hydrolysis Liu et al.

We investigated the effects of mitochondrial impairment in rat cerebral cortical neurons treated with oligomycin, antimycin, and rotenone, all of which inhibit different elements of the mitochondrial electron transport chain and thus cause a significant decline in ATP Huang et al. Our study revealed that a decline in ATP leads to multiple adverse effects: 1 A shutdown of the ubiquitination cascade occurred and was caused by inhibition of ubiquitin adenylation carried-out in an ATP-dependent manner by the E1 ubiquitin activating enzyme; 2 Disassembly of the 26S proteasome was observed and was triggered in part by the selective cleavage of Rpn10 by calpain, which is activated under conditions of ATP deficit.

No other proteasome subunit tested was cleaved by calpain. Rpn10 could act as a 26S proteasome gatekeeper sensitive to ATP deficits; 3 There was, accordingly, an increase in the activity of the 20S proteasome, which in concert with immunoproteasomes is postulated to degrade oxidatively modified proteins Grune et al.

These data are highly significant to AD because: 1 mitochondrial dysfunction Selfridge et al. In conclusion, both deleterious consequences of mitochondrial impairment, i.

Not only are mitochondria associated with UPS function in regards to ATP production and the generation of ROS, the UPS is also linked to mitochondrial function, as recent studies revealed that the UPS degrades mitochondrial proteins and thus contributes to mitochondrial quality control Taylor and Rutter, UPS impairment impacts several aspects of mitochondrial function that include: 1 mitochondrial dynamics Carlucci et al.

These factors are turned over by the UPS, and are perturbed in AD by either reduced expression, mis-localization, or an interaction with Tau Carlucci et al. In conclusion, it is clear that there is a mutual dependance between the UPS and mitochondria Livnat-Levanon and Glickman, New discoveries regarding the functional links between UPS and mitochondrial impairment and their roles in overall neuronal homeostasis could lead to novel and successful therapeutic approaches for AD Huang and Figueiredo-Pereira, SCI most commonly results from traumatic injuries to the spinal cord.

The initial mechanical disruption of white matter tracts is rapidly exacerbated by multiple secondary sequelae that include ischemia, inward calcium flux, infiltration with inflammatory cells and liberation of high levels of ROS which evolve over time to produce a chronic state of inflammation.

The acute and chronic production of ROS in the injured spinal cord may be expected to have multiple deleterious effects. Severe oxidative stress also impairs proteasome activity thereby increasing ubiquitin conjugates Shang and Taylor, Consistent with the notion that proteasome function is impaired after SCI, ubiquitinated proteins have been demonstrated to accumulate in human spinal cord axons in after SCI Ahlgren et al.

Ubiquitinated protein aggregates have also been found in neurons of dorsal root ganglia and spinal cord gray matter of rats after spinal cord compression Li and Farooque, The increase of ubiquitin and Uch-L1 was observed at the early stage of re-perfusion, after the 15 min spinal cord ischemia, and had resolved by 6 h after re-perfusion in experimental animal models.

These findings suggest a strong relationship between vulnerability of motor neurons and the ubiquitin-mediated stress response Yamauchi et al. A critical area of research is understanding mechanisms of neuronal death after SCI and identification of strategies to increase numbers of neurons that survive after the trauma, or so called neuroprotection.

Even if damage to the descending and ascending axons in white matter can not be prevented, interneurons present in gray matter may provide a means to rewire spinal cord circuits to restore some connectivity between the cortex and periphery Courtine et al.

Several lines of evidence link ubiquitin, Uch-L1 and E3 ubiquitin ligases to survival of such interneurons. Specifically, spinal cord interneurons with increased ubiquitin and Uch-L1 expression have been reported to have greater cell survival after SCI Noor et al. Similarly, ubiquitin and Uch-L1 up-regulation has also been observed in complete spinal cord transection Fry et al.

In addition, vulnerability of motor neurons of the spinal cord can be partially attributed to differences in ubiquitin-mediated stress responses after transient ischemia Sakurai et al.

Therefore, a failure to upregulate ubiquitin in motor neurons could represent a great disadvantage for motor neuron recovery Mengesdorf et al. Thus the significant changes in ubiquitin expression and cellular distribution in response to SCI, and its effects on the neuronal regeneration and myelination, suggest that the UPS could have a significant role in recovery from SCI caused by ischemia.

Once the acute inflammatory response to SCI has resolved, spinal cord neurons engage in a process of rewiring neuroplasticity and in efforts to extend new axons across the injured region neuroregeneration. Studies in Monodelphis domestica and mice suggest a linkage between neuroregeneration and expression levels of components of the UPS, although the underlying mechanisms are poorly understood.

For example, following spinal cord transection in Monodelphis domestica, axonal regeneration and regrowth of neuronal tissue was found at the injury site in animals injured at 7 days after birth P7 , which was associated with upregulation of ubiquitin mRNA and protein expression. However if injury occurred at postnatal 28 day p28 , little or no upregulation in ubiquitin expression occurred and no neuronal regeneration was observed Ji et al.

The levels of mono-ubiquitin were decreased at sites both caudal and rostral to the SCI injury site in aged animals, which also have reduced neuroregenerative capabilities; the magnitude of the decrease was found to be age-related. The reduction in ubiquitin levels may also be associated with involvement of ubiquitin in multiple functions and substrates in an organism outside of the proteasome system such as receptor internalization and modifications to chromatin structure Noor et al.

Moreover, the distribution of ubiquitin in response to the SCI also plays a role in the recovery of the spinal cord. For example, in motor neurons or interneurons of the ventral horn, ubiquitin is significantly increased in the cytosol after injury of postnatal 7 day p7 mice which demonstrate significant neuroregenerative capabilities. By contrast, in mature mice, where the capacity of neuron regeneration is lost, there is minimal change in ubiquitin levels in the cytosol of ventral horn neurons, in which ubiquitin was primarily localized to the nuclei Noor et al.

These findings suggest that the growth inhibitory or stimulatory factors that explain the difference in neuroregenerative capacity between young and old mice regulate ubiquitin expression and localization and support the view that certain levels of ubiquitin in injured neurons are essential for neuron regeneration. An open question is whether certain deubiquitinating enzymes such as Uch-L1 could be beneficial for the SCI.

It is notable therefore that Uch-L1 has been reported to promote neurogenesis and regulate differentiation of neuronal progenitors and has been proposed as a potential stem-cell based therapeutic target in the SCI Sakurai et al. Several neuroprotective drugs have been shown to reduce accumulation of aggregated, ubiquitinated proteins.

While it is logical to assume that elevation of Uch-L1 levels is beneficial after SCI, this possibility has not been tested. Further animal studies are needed in SCI models to determine if the overexpression of ubiquitin or Uch-L1 can lead to resistance to neural injury or promote neuroregeneration or neuroplasticity with benefits to functional recovery. Dysfunction of the proteasome may explain or contribute to the accumulation of ubiquitinated proteins after SCI Myeku et al. However, the role of the proteasome in neuronal regeneration is controversial and likely complex.

It has been found that treatment with proteasome inhibitors such as MG or lactacystin induces secondary axotomy of stretch-injured axons 72 h after the injury Du et al. The axonal stretch model replicates the mechanical forces acting on brain or spinal cord following traumatic brain injury TBI or SCI Staal et al. Of relevance to traumatically induced SCI, motor neurons are also more vulnerable to proteasome inhibitor induced neurotoxicity, which includes apoptotic nuclear changes and mitochondrial dysfunction Kikuchi et al.

In a rat SCI model, cAMP induced PKA activation reduced the accumulation of ubiquitinated protein that was caused by proteasome inhibition in the spinal cord, thus demonstrating a potential therapeutic approach in the prevention of neuronal damage after SCI Moore and Kennedy, ; Myeku et al.

On the other hand, the drug bortezomib, a 26S proteasome inhibitor currently used in treatment of multiple myeloma, was found to be effective in reducing brain ischemia size in clinical studies Shah and Di Napoli, by increasing ubiquitin expression in the infarct.

One might posit that treatment of bortezomib could also be beneficial after SCI to preserve motor neurons and to improve neuronal function Henninger et al. Furthermore, following nerve transection, MG, a peptide aldehyde inhibitor of the proteasome as well as multiple cysteine and serine proteases, delays the onset of Wallerian degeneration Zhai et al. Similar to the immunohistological studies, microarray analysis showed that inhibition of the proteasome may have both neuroprotective and pro-apoptotic response in primary neuron cells through upregulation of neuroprotective heat-shock proteins HSPs; Yew et al.

Of interest, the induction of Hsc70 by proteasome inhibitors prevents neuregulin-induced motor nerve demyelination and improves nerve conductance; these changes may be related to the clearance of c-Jun Li et al. However, proteasome inhibition activates antioxidant and HSP signaling pathways, which may result in neuroprotection early after SCI and an apoptotic response at later time points Yew et al.

The effects of proteasome inhibitors are thus complex, and likely depend on specificity of the inhibitor used and cell type, but also may be influenced by duration and timing relative to the initial spinal cord trauma. Additionally, proteasomes participate in myriad cellular processes in addition to housekeeping functions such as disposal of damaged proteins.

Differences in results of studies with proteasome inhibitors may reflect the relative activation state of one or more signaling pathways regulated by proteasomes, or of expression levels of E3 ligases or other components of ubiquitin machinery.

Such differences could explain, in part the divergent and at times apparently contradictory findings with proteasome inhibitors. Thus, further studies in animal models of SCI are needed to explore the role of proteasomes in neuroprotection and neuroregeneration and to define the timing of administration of proteasome inhibitors in the protection of spinal neuron recovery. APP is carried along the axon by fast axonal transport. It exists in both pre- and post-synaptic sites and has a role in synaptic function and axonal protein transport.

Generation, processing and resultant levels of APP have been identified to be very sensitive to CNS insults and have been extensively used as a biomarker of traumatic axonal injury. Levels of APP immunostaining provide a gold-standard for clinical identification of diffuse axonal injury both in brain and SCI Blumbergs et al.

Such findings suggest that both the initial injury and subsequent secondary injury caused by the activation of cascades which spread the injury away from the trauma site are involved in the above pathological changes. The accumulation of APP in traumatized axons at the epicenter of the injury, and also rostral and caudal to it, correlates with loss of motor neuron function, further demonstrating the crucial link between APP and the SCI.

These findings implicate impairment of both fast anterograde and retrograde axonal transport Medana and Esiri, ; Ward et al. Transport of these components to synapses is essential for normal neuronal function and survival Lazarov et al. It also induces the release of cytokines causing neuronal inflammation and defective endo-lysosomal trafficking Pimplikar et al. BACE1 is an aspartyl protease of the pepsin family that is mainly expressed in neuronal late Golgi and trans-Golgi TGN compartments as well as the cytoplasmic membrane Vassar et al.

Figure 3. Working hypothesis as to how Fbx2 facilitates beta-site amyloid precursor protein cleaving enzyme 1 BACE1 degradation. Multiple lines of evidence indicate that dysregulation of any of several components of the UPS, or mutations in genes that encode them, exacerbate AD progression and are deleterious to the recovery of function after SCI.

There are, however, many questions to be answered regarding the mechanisms by which these UPS components contribute to AD progression and facilitate or impede recovery of function after SCI. Finally, ubiquitin, Uch-L1, and the proteasome can be manipulated pharmacologically providing convenient methods for research applications and suggesting the possibility that further efforts in this field should include investigation of the potential utility of drugs that target these molecules.

The major obstacle in developing such therapies will be the ubiquitous presence of the UPS in eukaryotes which may require nanomedicine approaches or other tissue-targeting strategies to minimize adverse effects of such therapies. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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