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Chaperoned by Prebiotic Inorganic Polyphosphate Molecules: An Ancient Transcription-Independent Mechanism to Restore Protein Homeostasis

2014; Elsevier BV; Volume: 53; Issue: 5 Linguagem: Inglês

10.1016/j.molcel.2014.02.023

1097-4164

Harm H. Kampinga,

Endoplasmic Reticulum Stress and Disease

In this issue, Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar elegantly demonstrate how cells utilize an oxidation-regulated pathway that depletes cellular ATP, lowers proteostatic burden, and leads to accumulation of prebiotic, inorganic polyphosphates with chaperone-like activity for stress protection. In this issue, Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar elegantly demonstrate how cells utilize an oxidation-regulated pathway that depletes cellular ATP, lowers proteostatic burden, and leads to accumulation of prebiotic, inorganic polyphosphates with chaperone-like activity for stress protection. Inorganic polyphosphate (polyP) is a linear polymer of phosphates that can vary in length from ten to many hundred units and that was suggested to participate in prebiotic evolution. PolyP is not only present in bacteria, but is found in all higher eukaryotic organisms tested. It is found in many tissues (such as liver, kidney, lungs, brain, and heart) and localized in various subcellular compartments, including mitochondria (Kumble and Kornberg, 1995Kumble K.D. Kornberg A. J. Biol. Chem. 1995; 270: 5818-5822Crossref PubMed Scopus (254) Google Scholar). PolyP serves as storage for both phosphate and energy and is isoenergetic to ATP. PolyP can be generated directly from ATP by the enzyme polyphosphate kinase (PPK) and degraded to inorganic phosphate by exopolyphosphatase (PPX) (Figure 1). In the early 1990s, the Nobel Laureate Arthur Kornberg and his colleagues showed that bacterial PPK mutants had reduced polyP levels and were hypersensitive to a variety of stressors (Rao et al., 2009Rao N.N. Gomez-Garcia M.R. Kornberg A. Annu. Rev. Biochem. 2009; 78: 605-647Crossref PubMed Scopus (514) Google Scholar). However, the reason for this was actually never clearly understood. In this issue, Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar shed light on the mechanism behind this phenomenon. In their initial studies, Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar noticed that many of the stressors to which polyP apparently provided resistance were protein damaging agents (temperature, low pH, oxidants), while polyP itself was stable under such stress conditions. This prompted the authors to test whether polyP may play a role in protein homeostasis. First, they showed that, unlike wild-type strains, PPK mutant strains did not increase polyP levels upon proteotoxic stress. They also showed that PPK mutants were hypersensitive to heat and oxidative stress and displayed elevated levels of protein aggregates compared to wild-type strains. Second, PPK mutants showed no decreased heat shock response (HSR), which normally transcriptionally upregulates heat shock proteins for increased chaperone capacity (Akerfelt et al., 2010Akerfelt M. Morimoto R.I. Sistonen L. Nat. Rev. Mol. Cell Biol. 2010; 11: 545-555Crossref PubMed Scopus (961) Google Scholar). Rather, PPK mutants showed increased activation of the HSR, consistent with them suffering from more protein damage upon a similar stress than wild-type strains, thus suggesting that they lacked chaperone-like capacity. Importantly, Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar also used cell-free studies to show that the inorganic polyP could inhibit the aggregation of chemically and heat-denatured luciferase and citrate synthase in a concentration- as well as polyP length-dependent manner. As such, polyP maintained these substrates in a refolding competent state, which required the assistance of the canonical ATP-dependent Hsp70/DnaK machine (Figure 1A). This exciting finding provided direct evidence that these prebiotic, inorganic polyP molecules have chaperone-like activities that resemble the activity of the small HSPs (sHSPs) (Garrido et al., 2012Garrido C. Paul C. Seigneuric R. Kampinga H.H. Int. J. Biochem. Cell Biol. 2012; 44: 1588-1592Crossref PubMed Scopus (174) Google Scholar) (Figure 1B). A striking feature of this pathway is that polyP accumulation does not require transcriptional activation but is mediated by direct oxidation of the PPX enzyme, which leads to its transient inactivation. As well as leading to rapid accumulation of chaperone activity during acute stress, it also results in a drop in the levels of cellular ATP (Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar) (Figure 1). ATP depletion upon stress has generally been considered a result of cellular damage. Here, the challenging possibility is now emerging that ATP depletion actually may be part of an intricate dynamic response that on one hand acutely provides cells with an inorganic chaperone to restore protein homeostasis and on the other hand halts metabolic processes, hereby lowering the proteostatic burden of cells. Although the study by Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar does not exclude that ATP depletion is also due to cell damage, it does show that there is regulated ATP depletion upon stress (Figure 1A). Also in this respect, the polyP response resembles the response of sHSP: a sHSP chaperone is "activated" during stress, either directly via changes in oligomerization and/or (in mammalian cells) regulated by (de)phosphorylation reactions by protein kinases (PK) and protein phosphatases (PP). In analogy to the polyP pathways, this response not only increases the cellular chaperone capacity, but also has been linked to translational arrest, which lowers the proteostatic burden (Figure 1B) (Cuesta et al., 2000Cuesta R. Laroia G. Schneider R.J. Genes Dev. 2000; 14: 1460-1470PubMed Google Scholar, Carra et al., 2009Carra S. Brunsting J.F. Lambert H. Landry J. Kampinga H.H. J. Biol. Chem. 2009; 284: 5523-5532Crossref PubMed Scopus (108) Google Scholar). The finding that polyP has stress-protective activities by providing promiscuous chaperone activity is entirely novel and exciting. Yet additional research is required to provide more detailed mechanistic information on how polyP prevents protein aggregation. No evidence has yet been provided that polyP directly binds to and really "chaperones" clients. In fact, polyP and sHSPs seem to act on different steps of the unfolding and aggregation process. While polyP prevents unfolding by stabilizing the secondary structure of the clients (polyP maintains luciferase in a structured form up to 85C; Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar) (Figure 1A), sHSPs are thought not to prevent unfolding but rather bind to the unfolded substrates, preventing their aggregation or even changing the nature of the aggregates such that it can be "disaggregated" with the help of the Hsp70 machinery (Garrido et al., 2012Garrido C. Paul C. Seigneuric R. Kampinga H.H. Int. J. Biochem. Cell Biol. 2012; 44: 1588-1592Crossref PubMed Scopus (174) Google Scholar) (Figure 1B). How polyP prevents unfolding remains to be elucidated. Are they really client-binding chaperones? Or do they have (local) hydration effects like polyhydroxy compounds that also can nonspecifically raise the denaturation temperature of proteins (Lepock et al., 1988Lepock J.R. Frey H.E. Rodahl A.M. Kruuv J. J. Cell. Physiol. 1988; 137: 14-24Crossref PubMed Scopus (101) Google Scholar)? Since, however, the chaperoning effects are polyP length dependent (Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar), at least some kind of scaffolding action must be present as well. Irrespective of the mechanism, the existence of this acute, ancient, redox-regulated polyP pathway next to the acute sHSP oligomerization dynamics and the transcriptionally regulated HSR (to upregulate HSP expression) underscores the importance of maintaining protein homeostasis in living organisms. It suggests the following sequence of events to maintain protein homeostasis during and after stress (Figure 2): (1) Cells try to prevent unfolding (polyP) or irreversible aggregation (sHSP) by an acute transcriptionally independent mechanism; (2) in parallel, both pathways shut down metabolic processes to lower the burden of clients that require chaperoning; (3) upon stress relief, cells upregulate a repertoire of (ATP-dependent) chaperone proteins (HSR, UPR) that, in parallel with the restoration of ATP levels, help refolding of the chaperoned species or help degrade them via the proteasome; (4) as final rescue (only in eukaryotes), activation of (chaperone-assisted) autophagy may help to dispose otherwise nondigestible aggregates (Nivon et al., 2009Nivon M. Richet E. Codogno P. Arrigo A.P. Kretz-Remy C. Autophagy. 2009; 5: 766-783Crossref PubMed Scopus (102) Google Scholar). The data by Gray et al., 2014Gray M.J. Wholey W.-Y. Wagner N.O. Cremers C.M. Mueller-Schickert A. Hock N.T. Krieger A.G. Smith E.M. Bender R.A. Bardwell J.C.A. Jakob U. Mol. Cell. 2014; 53 (this issue): 689-699Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar mainly concern bacteria. It would be really interesting to test further if and how the reported polyP pathway contributes to stress resistance in higher eukaryotes like mammals and in which compartment this may play a role. Different compartments have different pathways to upregulate chaperones, such as the before-mentioned HSR for cytosol and nucleus and diverse forms of unfolded protein responses in the endoplasmatic reticulum and the mitochondria. How does the polyP pathway play a role here? Most of these compartments lack sHSP, and peroxisomes seem to entirely lack proteinaceous chaperones, yet stress resistance upon preconditioning does develop in these organelles (Hageman et al., 2007Hageman J. Vos M.J. van Waarde M.A. Kampinga H.H. J. Biol. Chem. 2007; 282: 34334-34345Crossref PubMed Scopus (35) Google Scholar). It will be intriguing to test how the polyP pathway might play a role in the development of stress resistance in eukaryotic organelles. Finally, a number of neurodegenerative diseases are characterized by the accumulation of protein aggregates, including Alzheimer's disease (β-amyloid, tau), Parkinson's disease (α-synuclein), and CAG repeat diseases (expanded polyglutamine-containing proteins). Upregulation of specific proteinaceous chaperones and induction of degradation systems have been shown to be protective against aggregation and toxicity in several disease models (Balch et al., 2008Balch W.E. Morimoto R.I. Dillin A. Kelly J.W. Science. 2008; 319: 916-919Crossref PubMed Scopus (1746) Google Scholar). It would be of interest to see whether the polyP pathway also can be protective in such disease models, in particular because extracellularly applied polyP can be taken up by mammalian cells (Rao et al., 2009Rao N.N. Gomez-Garcia M.R. Kornberg A. Annu. Rev. Biochem. 2009; 78: 605-647Crossref PubMed Scopus (514) Google Scholar), which could imply a feasible therapeutic strategy. Polyphosphate Is a Primordial ChaperoneGray et al.Molecular CellFebruary 20, 2014In BriefStudies of bacterial resistance to proteotoxic stress reveal that inorganic polyphosphate functions as a chaperone, stabilizing unfolding proteins and preventing aggregation. Here, Gray et al. help uncover polyphosphate's long known but largely unexplained role in protecting organisms against stress, and suggest that polyP may have served as one of nature's first chaperones. Full-Text PDF Open Archive