Cardiovascular Research

Cardiovascular Research 1997 33(1):8-12; doi:10.1016/S0008-6363(96)00141-1
© 1997 by European Society of Cardiology

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Copyright © 1997, European Society of Cardiology

Inappropriate ubiquitin conjugation: a proposed mechanism contributing to heart failure

Mark L Field and Joseph F Clark^*

MRC Biochemical and Clinical Magnetic Resonance Spectroscopy Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

Received 17 April 1996; accepted 11 June 1996

	Abstract

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
Ubiquitin; there is no doubt that ubiquitin is a "lucky" protein. It is lucky in many ways: lucky for scientific progress, lucky for biomedical scientists and lucky for life! If you have not already done so, why don't you get lucky and look for a role for ubiquitin in your experimental system. As Avram Hershko has said "there is plently to go around"! (Previousy quoted by Mayer et al. [1].)

KEYWORDS Ubiquitin; Heart failure; Cardiac hypertrophy

	1. Introduction

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
The precise sequence of events which cause a compensatory myocardial hypertrophy to become decompensated has proven elusive. A number of intracellular alterations constitute hypertrophic adaptation of the cardiomyocyte. These include alterations in signal transduction pathways[2–4], excitation-contraction coupling [5, 6] and contractile protein isozymes [7]. In addition there are a host of alterations in metabolic control [8], substrate selection [9] and energy transduction [10]. It is interesting that many of these hypertrophic intracellular adaptations appear to be equivalent in volume overload, pressure overload and cardiomyopathy. In this respect the intracellular biochemical specificity of the response of the myocyte to a chronic insult appears to be relatively restricted. It follows that certain aspects of the general hypertrophic response may not be appropriate for a given insult and therefore potentially detrimental. This is evidenced by the inevitable transition of a compensated hypertrophy to a failure state. As proposed by Chevalier et al. [11]: "heart failure thus appears less as a disease than as an index showing the limits of myocardial adaption ... the heart fails when all the extreme possibilities of adaption have been used." This has been termed the "trial and error" process of cardiomyocyte adaptation to overload. Traditionally, it has been thought that the limits of adaptation (in extremis) are approached when there is a mismatch between cardiomyocyte hypertrophy and capillary proliferation [12]. Recently, Oscar Bing [13] has suggested that at a cellular level, cell death through apoptosis may be a contributory mechanism in the transition of a compensated hypertrophy to a decompensated state. The suggestion that programmed cardiomyocyte death may be a contributory mechanism causing the transition to failure has provided a way forward from the present somewhat limited understanding of this process. As suggested by Bing [13], the greatest difficulty in the field has been separating cause from effect during the transitional process. The foremost question remains, which if any, are the true pathogenic alterations and which are cellular adaptations.

An area which has received relatively little consideration as a putative pathogenic mediator in the transitional process is the role of protein turnover per se. The approach to date has concentrated on documenting and investigating the functional consequences of alterations in the expression of proteins through transcription or translation, and their control. However, the total intracellular activity of an enzyme must also be a reflection of protein degradation. The control of cellular steady state degradation of key enzymes is mediated primarily through non-lysosomal, ubiquitin-proteosome degradation pathways [14]. In addition, the ubiquitin-proteosome system acts as an "intracellular surveillance system" that can destroy damaged or foreign proteins, akin to an "intracellular immune system"[1]. Clearly, the tight control of protein degradation is a requisite for intracellular homeostasis. An alteration in the specificity of this process is likely to be catastrophic for a cell. Indeed, several authors have suggested that ubiquitin-proteosome protein degradation may be intimately involved in the disease aetiologies of malignant neoplasia and several neurodegenerative diseases [1, 15]. This article hypothesises that altered or inappropriate ubiquitin conjugation (IUC) of key regulatory enzymes during the hypertrophic response may disturb homeostatic processes and thus be a contributory mechanism in the transition of a compensated hypertrophy to a decompensated failure state. It is proposed that IUC may amount to an "internal stress" which acts in synergy with the "external stress" of an overload, to hasten the transition of the heart into a failure state.

	2. Protein turnover

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
Protein turnover is the net result of DNA transcription, mRNA translation and protein degradation. For the purposes of this manuscript we are concerned with the chronic regulation of intracellular protein content through degradation. Most proteins have different half-lives with the regulatory proteins having the shortest lives allowing finer control of their concentration and therefore activity [16]. The regulatory enzymes of metabolism are maintained at very low concentrations in the cell, while equilibrium enzymes such as lactate dehydrogenase and soluble creatine kinase are maintained at relatively high concentrations. The combination of short half-life and low concentration makes enzymes such as phosphofructokinase ideally suited to key regulatory, rate determining positions in metabolism. The cellular mechanism of protein degradation is primarily through the lysosomal system or through conjugation with ubiquitin tags (76 amino acid polypeptide) which label a protein for degradation by the 26S proteosome [14, 16, 17]. It is the regulation of activity and specificity of the later process which is of concern in this article. What determines whether an enzyme is ubiquinated rapidly and thus has a short half-life? What factors may alter this intrinsic efficacy for self-ubiquination and thus change the steady state concentration of a protein? Central to the hypothesis developed in this article, does aberrant regulation of protein degradation during cardiac hypertrophy compromise the ability of myocytes to adapt successfully to a given stress?

	3. Mechanisms of ubiquitin mediated protein degradation

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
Ubiquitin conjugation to intracellular protein is achieved through a multistep process requiring three enzymes (E1, E2 and E3). For a comprehensive description, the reader is referred to detailed reviews on the subject [14, 16, 17]. In brief, ubiquitin is activated by linkage to E1 via a thioester bond. Activated ubiquitin is then translocated from E1 to E2, and finally E3, which then transfers it onto the target protein. Tagging of proteins for destruction usually involves polyubiquination. The so-called 26S proteosome is then responsible for ATP-dependent degradation of the target protein and release of ubiquitin [15]. The 26S proteosome consists of a 20S proteolytic unit and a 19S regulatory unit. The 19S subunit has a role in unfolding the protein, guiding it into the degradative tunnel of the 20S subunit and stimulating the proteolytic activity of the 20S subunit on the unfolded protein. The end result is a collection of small peptides from which ubiquitin is released and recycled.

	4. Control of ubiquitin mediated protein degradation

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
It is clear that tight controls must exist on the activity of the 26S proteosome and on which proteins are ubiquinated. The mechanisms of this regulation are discussed briefly in this monograph and given in detail elsewhere [14–17]. The proteolytic activity of the 20S subunit is spatially positioned within the degradative tunnel and thus isolated from the intracellular milieu. Together with the regulation of access by the 19S subunit, this positioning prevents non-specific proteolysis. The activity of the 20S subunit is further regulated by the efficacy for ubiquinated substrates, although this is not an obligatory requirement [15]. The factors which regulate ubiquination of a protein are central to the hypothesis developed here and are discussed further.

4.1. Primary structure
Ubiquitin is conjugated to proteins with an efficacy which partly depends on the presence of a bipartite signal within the primary structure, which is recognised by a ubiquitin-conjugating enzyme (E3) [14, 16, 17]. Proteins must contain a binding site for the ubiquitin-conjugating enzyme as well as a lysine residue in close proximity which accepts the activated ubiquitin polypeptide bound to E3. The N-terminal amino acid of a protein has been shown to be critical in determining the efficacy of E3-ubiquitin binding. The dependence of the in vivo half-life on the N-terminal amino acid has been designated the "N-end rule" [18, 19]. Enzymes which have a regulatory role in the cell, and require fine control, have so-called destabilising amino acids at their N terminus (i.e., arginine, lysine or aspartate), which promote binding of E3 and thus allow ubiquination. However, Ciechanover and Schwartz[14] have suggested that the bulk of proteins degraded by the ubiquitin system are recognised by signals other than the character of their N-terminal amino acid. Of particular note is the suggestion that short-lived proteins have so-called PEST (proline, glutamic acid, serine and threonine) sequences which are recognised by the ubiquitin-conjugating enzymes [20].

4.2. Intracellular location
Investigation of the degradation of hexokinase has shown that the efficacy with which a protein is ubiquinated depends on whether it is soluble or membrane bound [21]. Magnani et al. [21] have shown that hexokinase is more susceptible to ubiquination and degradation when soluble in the cytosol. It is becoming clear that the rate of degradation of hexokinase is dependent on its intracellular location, and by inference, the insulin status of the tissue. The putative dependence of the rate of hexokinase degradation on the insulin status of a tissue is an important regulatory mechanism at the basis of our hypothesis developed later in this monograph.

4.3. Control through phosphorylation
Evidence is emerging to suggest that phosphorylation of E1 and E2 may alter the rate at which they cause ubiquination[22, 23]. The two major signal transduction mechanisms thought to be involved are protein kinase C and tyrosine kinase respectively [22, 23]. The possible implications of these regulatory mechanisms are discussed later.

	5. Putative physiological roles for ubiquitin mediated protein destruction

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
Ubiquination of proteins has been implicated in the regulation of several cellular processes including cell cycle progression, antigen processing, transcription, embryonic development and apoptosis [1, 14–17]. Several of the mechanisms underlying the regulation of these processes by ubiquination are discussed with respect to disease aetiologies in the next section.

	6. Putative roles for inappropriate ubiquitin conjugation in general pathogenic processes

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
Certain pathogenic aetiologies clearly involve inappropriate ubiquination conjugation and some of these are listed below [14–17].

6.1. Degradation of proteins involved in transcription
Human papilloma virus types 16 and 18 are thought to produce neoplastic growth by promoting the ubiquination of p53 [24]. p53 is a so-called tumour suppressor protein by virtue of its activity as a transcription factor. With destruction of this transcription factor by viral induced ubiquination, cell division proceeds uninhibited predisposing to malignant transformation.

6.2. Degradation of proteins involved in the regulation of the cell cycle
Cyclins are proteins involved in the regulation of the cell cycle through their modulatory action on intracellular kinases [25]. Glotzer et al. [25] have suggested a process whereby ubiquitin conjugation to cyclin is responsible for destruction of the cyclin complex, enabling the cell to exit from the cell cycle. IUC through mutation of the cyclin complex may lead to reduced destruction of cyclin and therefore neoplasia.

6.3. Degradation of house keeper proteins
Mutated proteins are quickly ubiquinated and destroyed by cells. Interestingly, mutations that prevent recognition by the ubiquitin-proteosome system may allow such proteins to remain active in cells. This has been reported for mutations of the Jun oncoprotein [26]. Variants of c-Jun such as v-Jun escape from the ubiquitin-dependent degradation pathway and this has been correlated with cell transformation.

Having briefly discussed the role of the ubiquitin-proteosome degradative pathway in protein regulation, and its involvement in certain disease aetiologies, the possible role of IUC in heart failure shall now be discussed.

	7. The hypothesis: a role for inappropriate ubiquitin conjugation in heart failure?

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
As suggested, hypertrophy is the cellular response to an external stress and is believed to be a trial and error process of adaptation. Cardiac failure ensues when the extreme possibilities of adaptation have been used and cellular homeostasis is lost. Our hypothesis is that IUC during the hypertrophic response may be an additional internal stress on the myocyte which causes a loss in intracellular homeostasis and quickens the transition to failure. We discuss just three aspects of heart disease which might cause altered or inappropriate ubiquination; however, it is likely that each reader will be able to see a potential pathogenic role for IUC in their particular area of interest in the field of heart disease.

The first suggested mechanism by which IUC might compromise hypertrophic adaptation is based on evidence that a number of systems which control the ubiquination of proteins have been implicated in the pathogenesis of cardiac hypertrophy. Tyrosine kinase is able to activate ubiquination through phosphorylation of E2 [23]. An important hormone which acts through tyrosine kinase is insulin. Thus evidence suggests that insulin may control intracellular ubiquination through tyrosine kinase mediated phosphorylation of E2. Insulin also affects the subcellular distribution of hexokinase and thus the efficacy of key regulatory steps in metabolism [27]. Thus a second mechanism by which insulin affects the efficacy of intracellular ubiquination is by affecting the subcellular distribution of certain proteins. In addition, insulin affects the efficacy of ubiquination through its ability to induce gene expression of E2 [28]. Thus evidence suggests that insulin has a great regulatory influence on the ubiquination process at many different levels. Any disturbance of these regulatory pathways is likely to have a profound effect on intracellular protein turnover.

An important aspect of cardiac hypertrophy is insulin resistance due to changes in the signal transduction mechanisms of this hormone [27]. Interestingly, insulin resistance has previously been attributed as one of the pathogenic mechanisms of cardiac hypertrophy [27]. We believe that one pathogenic mechanism behind insulin resistance is a loss of control of the regulatory processes of protein ubiquination. As suggested the inability to tightly control the turnover of intracellular proteins is likely to lead to a rapid loss of homeostasis in a number of systems. Because the hypertrophic cell is already approaching the limits of adaptation, myocytes would be particularly prone to slight disturbances in intracellular homeostasis causing them to pass into a failure state. This may be one putative pathogenic mechanism underlying our hypothesis that IUC is an internal stress during hypertrophy, which hastens the transition to failure.

An important part of the hypertrophic process is the induction of the major heat shock protein genes; the so-called cell stress response [29]. A major stimulus of this response is the presence of abnormal or denatured proteins[30]. Interestingly, heat shock proteins are able to catalyse some of the key reactions of ubiquitin-dependent protein degradation, and ubiquitin is classified as one of the family of heat shock proteins [30]. Welch [31] has reported that although ubiquitin levels are increased after a cell stress primarily to remove denatured proteins, net protein degradation is actually reduced. Crucial to our hypothesis, Welch[31] suggests that the proteolytic systems themselves may be compromised immediately following a cell stress. We believe that the altered efficiency of the ubiquitin-proteosome system immediately following a cell stress response is likely to compromise the limits of cellular adaptation. This may be a second putative pathogenic mechanism underlying our hypothesis.

Lastly, we believe that IUC may also be involved in determining the viability of the ischaemic penumbra following an acute myocardial infarction. A similar hypothesis has been proposed by Mayer et al. [1] with respect to neuronal degeneration: "... protein ubiquination may be initially cytoprotective in a neurone and, if the process cannot combat the neuronal degenerative insult then ubiquitin-dependent protein catabolism is involved in destroying neurones in the final stages of nerve cell death." Thompson [32] states that during coronary occlusion, the area of infarction is surrounded by an ischaemic penumbra where the myocytes show signs of apoptosis. It is believed that if these cells are placed under additional cell stress they will exceed the so-called apoptotic threshold and die. Ubiquination is a central mechanism underlying apoptosis and we believe that one mechanism at the basis of the apoptotic threshold is a balance between approproate and inappropriate ubiquitin conjugation. Thus whether a myocyte in the ischaemic penumbra survives the insult will partly depend on the additional stress it is placed under, and therefore the presence of IUC.

Thus our hypothesis is based on the premise that during an overload the stresses placed on a cell is not solely through the external load but is also internal as a result of IUC. One may envisage that IUC of almost any enzyme system would disturb the intracellular homeostasis. Because the hypertrophic cell is already approaching the limits of adaptation, myocytes would be particularly prone to slight disturbances in intracellular homeostasis causing them to pass into a failure state. Experimental proof of a role for IUC in heart failure will require a protocol specifically tailored for each system in which this pathogenic mechanism is being considered.

	8. Conclusion

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 
We believe that inappropriate ubiquination of key regulatory enzymes during hypertrophic adaptation may disturb intracellular homeostasis and be a contributory mechanism in the transition towards failure. The alterations in intracellular and cellular homeostasis reach their maximum capacity for adaptation during compensatory hypertrophy and a slight additional stress such as IUC may provide the trigger for decompensation. While these proposals are purely speculative in the sphere of heart failure, similar mechanisms have been characterised in other diseases. We believe that the concept of an internal stress in novel and may prove an important concept in understanding heart failure.

Ubiquitin may well be a lucky protein, but just how lucky remains to be answered.

	Acknowledgements

 
The authors would like to acknowledge the support of Prof. G.K. Radda. We thank the MRC and BHF for financial support. M.L.F. is a Foulkes Foundation Fellow (1996/7). J.F.C. is a lecturer at Worcester College, Oxford.

	Notes

 
^* Corresponding author. Tel.: (+44-1865) 275289; fax: (+44-1865) 275259.

	References

Top Abstract 1. Introduction 2. Protein turnover 3. Mechanisms of ubiquitin... 4. Control of ubiquitin... 5. Putative physiological roles... 6. Putative roles for... 7. The hypothesis: a... 8. Conclusion References

 

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