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Ottaviani, Daniele (2016) Protein kinase ck2 phosphorylates the neuronal chaperone hsj1: a paradigmatic example of ubiquitin signaling regulation. [Ph.D. thesis]

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Abstract (english)

Protein kinase CK2 is an anti-apoptotic, constitutively active and ubiquitous Ser/Thr protein kinase. CK2 phosphorylates hundreds of substrates, characterized by the presence of acidic residues near the Ser/Thr target; its minimal consensus sequence is the motif S/TXXE/D/pS,pY,pT, where X is any amino acid and E/D/pX are acidic residues or previously phosphorylated ones. CK2 stabilizes anti-apoptotic signalling pathways and therefore is regarded as a pro-survival kinase. It is highly expressed in cancer where it sustains abnormal cell growth and survival. Therefore, CK2 represents a promising drug target against which several inhibitory compounds have been developed so far. However, there are now compelling evidences for a critical function of CK2 in neurons and a role in neurodegeneration has been suggested, but never studied in detail. Interestingly, we noticed that the CK2 consensus is superimposable to a sequence inside the ubiquitin interacting motif (UIM) of the neuronal-specific chaperone HSJ1. HSJ1 has a neuroprotective role and controls the folding, misfolding, aggregation and degradation of protein clients, thus maintaining their homeostasis (proteostasis). Consistently, functional mutations in its gene have been associated to neurodegenerative disease (NDs). The project presented in this thesis is based on the working hypothesis that phosphorylation of residues conforming to the CK2 consensus on HSJ1 could affect its functions.
HSJ1 belongs to the DNAJ protein family. It is preferentially expressed in neuronal tissues and contains an N-terminal J domain and two UIM domains near the C-terminus. It is codified by the DNAJB2 gene and alternatively spliced to produce two isoforms: HSJ1a and HSJ1b. The former is mainly located in the nuclear and cytosolic compartments, the latter is anchored to the cytosolic face of the endoplasmic reticulum. HSJ1b participates in the endoplasmic reticulum-associated protein degradation (ERAD) system as a folding controller of membrane-associated proteins. HSJ1a cooperates with Hsp70 in binding and delivering ubiquitylated proteins to proteasomal degradation. In particular, it suppresses the deposition of aggregation-prone proteins such as SOD1 (Superoxide Dismutase 1) in amiotrophic lateral sclerosis, polyglutamine expanded huntingtin in Huntington’s disease, ataxin-3 in spinocerebellar ataxias, and promotes the refolding of a Parkin mutant in Parkinson’s disease. Genetic studies have provided further evidences for a role of HSJ1 in neuronal survival, as mutations in DNAJB2 cause distal hereditary motor neuropathy and Charcot-Marie-Tooth type 2. Nevertheless, the biochemical mechanisms by which HSJ1 acts in these pathologies are only partially understood.
The results we obtained suggest that CK2 is a prominent HSJ1 phosphorylating kinase. As mentioned above, HSJ1 UIMs display canonical CK2 consensus sites. Therefore, we first performed in vitro phosphorylation experiments on HSJ1a. We expressed the protein in HEK-293T cells and confirmed the phosphorylation of HSJ1 by means of cell loading with [32P]phosphate, followed by the immunoprecipitation of the chaperone. In this assay, the HSJ1 phosphorylation was assessed by autoradiography of the immunoprecipitated protein and the CK2-dependendece by demonstrating its sensitivity to the CK2 inhibitor CX-4945. A mass spectrometry analysis revealed that Ser247, Ser250 and Ser264 are phosphorylated and are inside the second UIM. Then, we produced Serine-to-Alanine mutants of each CK2 target-residue, both in prokaryotic and eukaryotic expression vectors. We performed in vitro kinase assays on recombinant purified proteins or upon their expression in HEK-293T cells and subsequent immunoprecipitation. Collectively, the data demonstrated that Ser250 is the main phospho-site on HSJ1. The Ser264 only marginally contributes to the overall HSJ1 phosphorylation and Ser247 is a hierarchical site. In fact, Ser247 does not fulfil the CK2 minimal consensus sequence, because it does not have an acidic residue in +3 position. However, once Ser250 is phosphorylated the residue becomes acidic and fits the consensus sequence. This implies that a hierarchical phosphorylation can occur in HSJ1, where the previous phosphorylation of Ser250 primes Ser247 for subsequent phosphorylation.
Then, we successfully designed and developed a strategy for the production of phospho-specific antibodies against the main Ser247/Ser250 phospho-sites. The signal of he purified antibodies strongly reduced in response to cell treatments with different CK2 specific inhibitors. They were also useful to confirm the phosphorylation of both HSJ1 isoforms, a and b, in cells.
We then aimed at investigating the effects of HSJ1a phosphorylation on its functions and in particular on the binding to its ubiquitylated clients. To this purpose, we exploited the transfection of phospho-null and phospho-mimetic mutants into HEK-293T cells. The analysis of the ubiquitylated proteins co-immunoprecipitated with WT or mutated HSJ1a followed. Results showed that HSJ1a is able to bind more ubiquitylated clients when the phosphorylation at its CK2 sites is prevented. Moreover, we also found that these not-phosphorylated forms have enhanced activities in delivering the reporter luciferase protein to proteasomal degradation. We concluded that the phosphorylation of HSJ1a by CK2 impairs its chaperone function.
With this study, we disclosed an unanticipated HSJ1/CK2 connection with important implications for the molecular mechanisms of neurodegeneration and hopefully for the development of associated therapies. The HSJ1 co-chaperone function is critical in preventing neurodegeneration and is enhanced by the dephosphorylation of the sites targeted by CK2; therefore, treatments with CK2
inhibitors could be explored in the future as novel therapeutic compounds in NDs.
Since we observed that UIMs residues are evolutionary conserved in other proteins and superimposable to the CK2 consensus, with this work we suggest that other UIM-containing proteins could be phosphorylated. Indeed, we already showed that the UIM-containing proteasome subunit S5a is phosphorylated by CK2. Therefore, the CK2/HSJ1 connection could be a paradigmatic example of a broader regulation mechanism able to influence the processing of ubiquitylated proteins.

Related Projects
Protein kinase CK2 appeared to be a prominent druggable target after the discovery of its deregulated activity in cancer. Cancer cells were demonstrated to be more sensitive to the inhibition of CK2 than their healthy counterparts. This observation promotes the design and testing of several inhibitory molecules some of which are currently patented and/or in clinical trials. However, the use of inhibitors was also of invaluable support in helping understanding the role of CK2 in other pathologies. From the work described in the main project, is now evident that CK2 inhibitors should be indeed considered in a therapeutic perspective for neurodegeneration.
Despite the wide use and availability of CK2 inhibitory compounds, the characterization of their mechanism of action and tolerability are still under intensive investigations. Most inhibitors have been designed as competitors for the ATP-binding pocket on protein kinases. However, different strategies have been explored in order to increase the therapeutic efficacy. We designed, developed and characterized two alternative inhibition strategies. A first project concerned the analysis of a chimeric molecule named CK2-MCP, designed to specifically target the consensus recognized by CK2 in its substrates. We showed that CK2-MCP is able to double-hit both substrates and the kinase itself. A second project concerned a different kind of ’double-hit’ strategy addressed by a compound named TDB. It was designed to multitarget both CK2 and Pim-1, another kinase implied in cancer onset and progression. We compared TDB and CX-4945 in term of their ability to inhibit the CK2 activity and to reduce cancer cells viability. Our results, in different treatments times and protocols, revealed that TDB displays a higher persistence of the inhibitory effect on CK2. This peculiarity produced a more pronounced toxicity for cancer cells, despite the superiority of CX-4945 efficacy in vitro. We suggest that the optimization of the cellular persistence of the CK2-inhibitor complex is a crucial aspect that should be considered during the optimization of inhibitory compounds.

Abstract (italian)

La proteinchinasi CK2 è una serina/treonina chinasi espressa ubiquitariamente in tutti i tessuti dove svolge un importante ruolo anti-apoptotico. Questo enzima fosoforila una molteplicità di substrati coinvolti nella proliferazione e sopravvivenza cellulari ed accomunati dalla presenza di un “sito consenso”. Questo sito presenta un residuo di serina (S) o treonina (T) inserito in un intorno di amminoacidi acidi che definiscono il motivo minimo S/TXXE/pS/pY/pT: X rappresenta un generico amminoacido mentre E/D/pX sono residui acidi o fosforilati in precedenza. Elevati livelli di espressione di CK2 sono stati riscontrati in neoplasie dove il suo ruolo anti-apoptotico promuove la proliferazione e l’invasione delle cellule cancerose. Di conseguenza, l’enzima è considerato un importante bersaglio, contro cui sono stati sviluppati negli anni diversi inibitori in grado di ridurne l’attività. Tuttavia, vi sono ormai evidenze del coinvolgimento di CK2 nello sviluppo e funzione neuronali; inoltre, è stato suggerito, ma non studiato nel dettaglio, che il ruolo di CK2 nei neuroni possa avere ripercussioni nella progressione e sviluppo di malattie neurodegenerative. Abbiamo notato che uno dei “sito consenso” riconosciti da CK2 nei suoi substrati, coincide con una sequenza all’interno di un motivo in grado di legare l’ubiquitina (UIM) della proteina HSJ1. HSJ1, espressa prevalentemente in cellule neuronali, agisce da “chaperone molecolare”: controlla l’assemblaggio (folding), disassemblaggio, aggregazione e degradazione delle proteine che riconosce mediante i suoi domini UIM, mantenendo i loro livelli in equilibrio dinamico (proteostasi). Ne consegue che HSJ1 esercita un ruolo neuroprotettore. Infatti, sono state identificate alcune mutazioni a carico del suo gene DNAJB2, ed associate all’insorgenza di alcune malattie neurodegenerative. Inoltre, alcune di queste mutazioni sono in grado di compromettere la funzione neuroprotettiva di HSJ1.
Il progetto di questa tesi si pone come obiettivo di dimostrare che la fosforilazione di alcuni residui di HSJ1 da parte di CK2 è in grado di influenzarne la funzione. HSJ1 è una proteina appartenente alla famiglia detta DNAJ cui membri sono accomunati dalla presenza del dominio proteico detto “dominio J”. HSJ1, come detto prima, contiene anche due domini UIM localizzati al C-terminale. Il genoma umano codifica un unico trascritto, poi processato per produrre due isoforme: HSJ1a, espressa nel citosol, ed HSJ1b, ancorata alla faccia esterna del reticolo endoplasmatico. Entrambe le isoforme cooperano con la proteina Hsp70 nel legare e dirigere proteine ubiquitilate al proteasoma per essere degradate. In particolare, HSJ1a promuove la degradazione di proteine prone all’aggregazione. Infatti, il non corretto folding proteico può causarne la deposizione come aggregati intracellulari tossici, detti amiloidi, e considerati come un sintomo indicativo nella diagnosi di molte malattie neurodegenerative. Ad esempio, HSJ1a è tra i mediatori della degradazione della proteina SOD1 (superossido dismutasi 1) coinvolta nella sclerosi laterale amiotrofica, di proteine con tratti poliglutamminici espansi ed associati alla malattia di Huntington, ed infine della proteina ataxina-3, considerata agente eziologico nelle atassie spinocerebellari. Inoltre, HSJ1a coadiuva il folding della proteina parkina coinvolta nell’insorgenza di alcune forme del morbo di Parkinson. Studi di associazione genetica hanno anche dimostrato che alcune mutazioni nel gene DNAJB2 causano neuropatie motorie ereditarie e la malattia di Charcot Marie Tooth - tipo 2. Tuttavia i meccanismi molecolari mediante cui HSJ1 agisce sono stati compresi solo parzialmente.
I risultati che abbiamo ottenuto dimostrano che HSJ1 è fosforilata da CK2. Come detto in precedenza, HSJ1 presenta alcuni residui amminoacidici all’interno del suo dominio UIM che sono potenzialmente fosforilabili da CK2. Abbiamo quindi svolto un’analisi in spettrometria di massa della proteina fosforilata che ci ha permesso di identificare i siti riconosciuti da CK2 che sono: i residui di serina alle posizione 247, 250 e 264. Successivamente, abbiamo espresso HSJ1 in cellule mediante vettori di espressioni eucariotici. Questi esperimenti erano atti a dimostrare che HSJ1 è fosforilata anche in cellule da CK2. Infatti, trattamenti in cui l’attività dell’enzima è stata ridotta mediante l’uso dell’inibitore CX-4945, hanno dimostrato che HSJ1 è substrato di CK2. Inoltre, abbiamo operato singole sostituzioni amminoacidiche a carico dei residui serinici riconosciuti dall’enzima che sono stati mutati in residui alaninici. Ciò ha confermato ulteriormente i siti da noi identificati su HSJ1 come fosforilati da CK2, sia in vitro che in cellule. Collettivamente, i dati raccolti confermano che il sito principale di fosforilazione è la serina alla posizione 250. Il residuo alla posizione 264 contribuisce solo marginalmente. La serina 247 invece è definita come un sito gerarchico. Infatti, l’intorno amminoacidico del residuo alla posizione 247 non soddisfa i requisiti minimi per essere definito “sito consenso” per CK2. Ciò può avvenire solo una volta che la serina 250 è fosforilata. Di conseguenza, la serina 247 potrà essere riconosciuta da CK2 grazie al residuo acidico in posizione +3, in questo caso rappresentato dalla serina 250 fosforilata in precedenza.
Abbiamo poi ideato e sviluppato una strategia che ci ha permesso di produrre anticorpi in grado di riconoscere in maniera specifica le serine alla posizione 247 e 250, solo nel caso esse siano fosforilate da CK2. Questo strumento è stato utilizzato per confermare che entrambe le isoforme di HSJ1, a e b, sono fosforilate in cellule. Inoltre, abbiamo potuto verificare che la fosforilazione di HSJ1a è sensibile all’inibizione esercitata da un ampio pannello di inibitori specifici di CK2. Abbiamo poi analizzato se la fosforilazione di HSJ1 possa avere un impatto sulla sua funzione di legare proteine ubiquitinate da convogliare al proteasoma per la degradazione. Abbiamo quindi espresso HSJ1 in cellule, nella sua forma originale o mutata nei siti di fosforilazione. Mediante la co-precipitazione della proteina, a cui permangono legati i partner ubiquitilati, abbiamo potuto dimostrare che la fosforilazione dei siti-chiave da noi identificati causa una minor funzionalità del dominio UIM di HSJ1. Al contrario, la prevenzione della fosforilazione aumenta la capacità del dominio UIM di legare proteine ubiquitilate e di trasportarle al proteasoma, come abbiamo verificato nei riguardi della proteina luciferasi. Abbiamo potuto così concludere che la fosforilazione di HSJ1 da parte di CK2 contrasta la sua funzione di “chaperone molecolare”. Questo studio ci ha consentito di dimostrare una nuova connessione tra HSJ1 e CK2, in grado di aiutarci a comprendere meglio i meccanismi molecolari che sottendono l’insorgenza e lo sviluppo delle malattie neurodegenerative. Vi sono inoltre importanti risvolti terapeutici, dal momento che l’uso di inibitori di CK2 potrebbe essere proposto per aumentare la funzionalità di HSJ1.
Infine, abbiamo notato che alcuni residui amminoacidici all’interno del motivo UIM sono evolutivamente conservati e coincidono con la “sequenza consenso” minima richiesta per la fosforilazione da parte di CK2. Pertanto consideriamo altamente probabile che altre proteine contenenti domini UIM possano essere substrati di CK2, come dimostriamo in questa tesi anche per la proteina S5a, una subunità del proteasoma. Pertanto, HSJ1 vuole porsi come esempio paradigmatico di una possibile più ampia regolazione da parte di CK2 in grado di influenzare questa via di segnale mediata dall’ubiquitina.

Progetti complementari
Dalla scoperta del coinvolgimento della proteinchinasi CK2 nel cancro, le cellule neoplastiche si sono rivelate essere più sensibili all’inibizione della sua attività, rispetto alle cellule sane. Questo ha favorito lo sviluppo di molti inibitori alcuni dei quali sono al momento brevettati e/o in trials clinici. Tuttavia, come suggerito dal lavoro principale di questa tesi, queste molecole si sono rivelate utili strumenti per meglio comprendere il ruolo di CK2 in altre patologie (i.e. nelle malattie neurodegenerative) e potrebbero essere presi in considerazione per il loro
Nonostante l’uso diffuso di inibitori di CK2, la comprensione del loro meccanismo d’azione e tollerabilità non sono stati ancora del tutto chiariti. Molti degli inibitori sviluppati fino ad ora sono ATP-competitivi, quindi in grado di legarsi alla tasca per i nucleotidi in CK2. Tuttavia, si stanno prendendo in considerazione strategie differenti per cercare di aumentarne l’efficacia terapeutica. In progetti complementari all’argomento principale di questa tesi, abbiamo analizzato due strategie di inibizione alternative. La prima ha riguardato lo sviluppo di una molecola chimerica chiamata CK2-MCP. Questa è in grado di legare per complementarietà il “sito consenso” di CK2 nei suoi substrati, impedendo all’enzima di accedervi per fosforilarli. Abbiamo però dimostrato che questa classe di composti è in grado di legare sia i substrati di CK2, come atteso, che l’enzima stesso.
Nel secondo progetto complementare, abbiamo invece preso in considerazione un altro tipo di strategia duale, mediante l’uso di un inibitore sviluppato recentemente, detto TDB. Questo composto è in grado di inibire sia CK2 che Pim-1, un’altra proteinchinasi implicata nello sviluppo tumorale. Abbiamo comparato i composti CX-4945 e TDB per la loro capacità di inibire CK2 e di ridurre la vitalità delle cellule cancerose. Differenti tempi e condizioni di trattamento hanno dimostrato la più alta persistenza dell’inibizione di CK2 esercitata dal TDB in cellule, nonostante la superiorità del CX-4945 in vitro. La maggior durata dell’inibizione di CK2, indipendentemente dal fatto che il TDB inibisca anche Pim-1, sembra essere responsabile dei maggiori effetti citotossici indotti dal TDB nelle cellule tumorali. Questo suggerisce che l’ottimizzazione di inibitori di CK2 in cellule debba tenere conto anche di questo parametro.

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EPrint type:Ph.D. thesis
Tutor:Ruzzene, Maria
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:12 January 2017
Anno di Pubblicazione:23 December 2016
Key Words:CK2, DNAJB2, HSJ1, Ubiquitylation, UIM
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:9817
Depositato il:16 Nov 2017 10:57
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