Small Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein

Sumoylation is an important post-translational modification that provides a rapid and reversible means for controlling the activity, subcellular localization, and stability of target proteins. We have examined the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to tau and α-synuclein, two natively unfolded proteins that define several neurodegenerative diseases. Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences, and mutational analyses identified Lys340 as the major sumoylation site. Although both tau and α-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Tau is a microtubule-associated protein, whose ability to bind and stabilize microtubules is negatively regulated by phosphorylation. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation. This suggests that SUMO modification may preferentially target a free soluble pool of the substrate. These findings revealed a new, possibly regulatory, modification of tau and α-synuclein that may also have implications for their pathogenic roles in neurodegenerative diseases. Sumoylation is an important post-translational modification that provides a rapid and reversible means for controlling the activity, subcellular localization, and stability of target proteins. We have examined the covalent attachment of the small ubiquitin-like modifier (SUMO) proteins to tau and α-synuclein, two natively unfolded proteins that define several neurodegenerative diseases. Both brain proteins were preferentially modified by SUMO1, as compared with SUMO2 or SUMO3. Tau contains two SUMO consensus sequences, and mutational analyses identified Lys340 as the major sumoylation site. Although both tau and α-synuclein are targets for proteasomal degradation, only tau sumoylation was affected by inhibitors of the proteasome pathway. Tau is a microtubule-associated protein, whose ability to bind and stabilize microtubules is negatively regulated by phosphorylation. Treatment with the phosphatase inhibitor, okadaic acid, or the microtubule depolymerizing drug, colchicine, up-regulated tau sumoylation. This suggests that SUMO modification may preferentially target a free soluble pool of the substrate. These findings revealed a new, possibly regulatory, modification of tau and α-synuclein that may also have implications for their pathogenic roles in neurodegenerative diseases. Small ubiquitin-like modifier proteins (SUMO) 2The abbreviations used are: SUMO, small ubiquitin-like modifier; E1, SUMO activating enzyme; E2, SUMO-conjugating enzyme; E3, SUMO ligase. 2The abbreviations used are: SUMO, small ubiquitin-like modifier; E1, SUMO activating enzyme; E2, SUMO-conjugating enzyme; E3, SUMO ligase. display similarities to ubiquitin in both the structure and the biochemistry of their conjugation (for review, see Ref. 1Dohmen R.J. Biochim. Biophys. Acta. 2004; 1695: 113-131Crossref PubMed Scopus (200) Google Scholar). SUMO isoforms are expressed in humans and display cell type-specific expression levels and distinct, although not exclusive, subcellular localizations (2Su H.-L. Li S. S.-L. Gene (Amst.). 2002; 296: 65-73Crossref PubMed Scopus (127) Google Scholar). Each SUMO paralog is expressed as a precursor protein that undergoes processing by a C-terminal hydrolase (3Kamitani T. Nguyen H.P. Yeh E.T.H. J. Biol. Chem. 1997; 272: 14001-14004Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). Once cleaved, the mature protein has a diglycine motif exposed at the C terminus and is ready to enter a multistep enzymatic pathway, which is similar but quite distinct from ubiquitination. Mature SUMO proteins are primed in an ATP-dependent manner by the SUMO-activating (E1) enzyme Sua1/hUba2 (4Johnson E.S. Schwienhorst I. Dohmen R.J. Blobel G. EMBO J. 1997; 16: 5509-5519Crossref PubMed Scopus (439) Google Scholar, 5Desterro J.M.P. Rodriguez M.S. Kemp G.D. Hay R.T. J. Biol. Chem. 1999; 274: 10618-10624Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar). Activated SUMO is then transferred, through a trans-esterification reaction, to a unique conjugating (E2) enzyme, Ubch9 (6Johnson E.S. Blobel G. J. Biol. Chem. 1997; 272: 26799-26802Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 7Desterro J.M.P. Thomson J. Hay R.T. FEBS Lett. 1997; 47: 297-300Crossref Scopus (302) Google Scholar). The final step is the formation of an isopeptide bond between the C-terminal glycine of SUMO and the lysine ϵ-amino group of the target substrate. A majority of the acceptor lysine residues are found within a SUMO consensus motif ΨKX(E/D), in which Ψ corresponds to a hydrophobic residue. Although E1 and E2 are sufficient for SUMO conjugation to various substrates (8Okuma T. Honda R. Ichikawa G. Tsumagari N. Yasuda H. Biochem. Biophys. Res. Commun. 1999; 254: 693-698Crossref PubMed Scopus (181) Google Scholar, 9Rodriguez M.S. Desterro J.M.P. Lain S. Midgley C.A. Lane D.P. Hay R.T. EMBO J. 1999; 18: 6455-6461Crossref PubMed Scopus (557) Google Scholar), it is assumed that SUMO E3 ligases catalyze sumoylation at non-consensus sites, increase the rate of modification, or ensure substrate specificity (10Johnson E.S. Gupta A.A. Cell. 2001; 106: 735-744Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar, 11Pichler A. Gast A. Seeler J.-S. Dejean A. Melchior F. Cell. 2002; 108: 109-120Abstract Full Text Full Text PDF PubMed Scopus (631) Google Scholar, 12Kahyo T. Nishida T. Yasuda H. Mol. Cell. 2001; 8: 713-718Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar, 13Kagey M.H. Melhuish T.A. Wotton D. Cell. 2003; 113: 127-137Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar). Sumoylation is a highly dynamic and reversible process as specific proteases can rapidly remove SUMO from their substrates (for review, see Ref. 14Melchior F. Schergaut M. Pichler A. Trends Biochem. Sci. 2003; 28: 612-618Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar). In contrast to ubiquitin, which mainly tags proteins for proteasome-mediated degradation, covalent modification by SUMO can have a number of functional consequences for the target proteins. For example, sumoylation modulates protein-protein interactions, affects subcellular localization and, in some cases, antagonizes the proteasome pathway by competing with ubiquitin (for review, see Ref. 1Dohmen R.J. Biochim. Biophys. Acta. 2004; 1695: 113-131Crossref PubMed Scopus (200) Google Scholar). Despite the rapidly growing number of SUMO substrates identified, in most cases, the physiological function and regulation of sumoylation remain elusive and may vary according to the nature of the target. Tau and α-synuclein belong to the family of natively unfolded proteins as they display an extended conformation in vitro with little ordered secondary structure (15Schweers O. Schönbrunn-Hanebeck E. Marx A. Mandelkow E. J. Biol. Chem. 1994; 269: 24290-24297Abstract Full Text PDF PubMed Google Scholar, 16Weinreb P.H. Zhen W. Poon A.W. Conway K.A. Lansbury Jr., P.T. Biochemistry. 1996; 35: 13709-13715Crossref PubMed Scopus (1283) Google Scholar). Both proteins are highly soluble and heat-resistant. They are highly expressed in the brain and are associated with several neurodegenerative disorders including Alzheimer and Parkinson disease (reviewed in Ref. 17Goedert M. Curr. Opin. Genet. Dev. 2001; 11: 343-351Crossref PubMed Scopus (80) Google Scholar). As with other amyloidogenic proteins, tau and α-synuclein undergo a pathological transition from random coil to a β-pleated sheet conformation that is accompanied by extensive aggregation and fibril formation (18Barghorn S. Davies P. Mandelkow E. Biochemistry. 2004; 43: 1694-1703Crossref PubMed Scopus (178) Google Scholar, 19Conway K.A. Harper J.D. Lansbury Jr., P.T. Biochemistry. 2000; 39: 2552-2563Crossref PubMed Scopus (678) Google Scholar, 20Serpell L. Berriman J. Jakes R. Goedert M. Crowther R.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4897-4902Crossref PubMed Scopus (636) Google Scholar). Post-translational modifications affect both protein structure and function and may also contribute to protein dysfunction. Tau is a phosphoprotein with up to 30 tightly regulated phosphorylation sites, and hyperphosphorylation is a common feature of paired helical filaments in Alzheimer disease (21Grundke-Iqbal I. Iqbal K. Tung Y.-C. Quinlan M. Wisniewski H.M. Binder L.I. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 4913-4917Crossref PubMed Scopus (2786) Google Scholar). Similarly, α-synuclein inclusions in the form of Lewy bodies are a pathological hallmark of Parkinson disease and other α-synucleinopathies (22Spillantini M.G. Goedert M. Ann. N. Y. Acad. Sci. 2000; 920: 16-27Crossref PubMed Scopus (374) Google Scholar). In addition to phosphorylation (23Okochi M. Walter J. Akihiko K. Nakajo S. Baba M. Iwatsubo T. Meijer L. Kahle P.J. Haass C. J. Biol. 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Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). was used to the as SUMO were and by tau in expression was and α-synuclein was Tau α-synuclein and the were by according to the and by and were in modified with were in at according to the For were in the of of tau or α-synuclein, in the or of of isoforms as was used to the of to of was and were for an were for the final with okadaic or were and in of SUMO and were in were to and by The protein was the were with of with and for at The were by with and with SUMO were in and by were by and and were from was by Davies of was from and were used as secondary were by according to the were of which Sumoylation of Tau and and α-synuclein are two natively unfolded proteins found in inclusions that define several neurodegenerative diseases. Both proteins are regulated through various post-translational modifications as phosphorylation (21Grundke-Iqbal I. Iqbal K. Tung Y.-C. Quinlan M. Wisniewski H.M. Binder L.I. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 4913-4917Crossref PubMed Scopus (2786) Google Scholar, M. Walter J. Akihiko K. Nakajo S. Baba M. Iwatsubo T. Meijer L. Kahle P.J. Haass C. J. Biol. Chem. 2000; 275: 390-397Abstract Full Text Full Text PDF PubMed Scopus (414) Google and H. D. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L. D. K. J. H. A. M. E. J. G. J. A. R. Y. J. M. Mol. Genet. 2004; PubMed Scopus Google Scholar, T. J. PubMed Scopus Google Scholar, T. Iwatsubo T. M. Biochemistry. PubMed Scopus Google Scholar). Sumoylation an important in have also sumoylation in H. J. H. K. H. I. H. Biochem. Biophys. Res. Commun. 2002; PubMed Scopus Google Scholar, T. H. M. K. Yasuda H. 2002; PubMed Scopus Google Scholar, J.M. I. D. Mol. Genet. 2002; 11: PubMed Google Scholar, Y. R.J. E. 2003; PubMed Scopus Google Scholar, F. Lett. PubMed Scopus Google Scholar), and proteins in were found to SUMO targets J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, N. J. E. 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This a specific conjugation to tau and cell for the revealed that it as a with the of tau and α-synuclein modification that both natively unfolded proteins tau and α-synuclein can preferentially by SUMO of Tau and majority of are by the consensus motif ΨKX(E/D), Ψ corresponds to a hydrophobic is the target lysine for covalent is acid, and the final is a or residue. Tau and α-synuclein have two SUMO consensus and was used to sumoylation at sites, and were The tau and were expressed at similar levels as the protein not The modification of tau This tau was to the as the that the consensus motif is not a target for In sumoylation of the tau was and were These findings that Lys340 of the major acceptor for both and of the SUMO modification in the of the two SUMO consensus within the C-terminal of The are as modification by of α-synuclein as compared with α-synuclein or were with and SUMO substrates were by and by sumoylation of α-synuclein was also the of a specific consensus similar of the two target lysine residues and was of the α-synuclein in a in the of sumoylation as compared with This that may of but it is to a target residue. Despite the other SUMO not to with within the by the and the the which the protein not other as the and a α-synuclein and P. E. were were not for both in the for α-synuclein not the that the α-synuclein suggests that is not a major SUMO target that by conjugation at also in and of by the as In addition to and α-synuclein contains other lysine residues that are mainly within the has also that sumoylation is not to consensus M.H. Melhuish T.A. Wotton D. Cell. 2003; 113: 127-137Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar, M. Melchior F. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, W. H. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), and modification may at or of other This is the for α-synuclein which is to lysine residues within the of the protein and not or T. Iwatsubo T. M. Biochemistry. PubMed Scopus Google Scholar). 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J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). cell was for α-synuclein and as compared with α-synuclein not the functional for conjugation of α-synuclein to Although tau and α-synuclein belong to the family of natively unfolded proteins and are also SUMO the of proteasome that both proteins are most regulated through distinct This is in their in of sumoylation similar by in the of Tau Sumoylation by and is to have and functional proteins. natively unfolded and proteins are regulated by post-translational modification (reviewed in Ref. Curr. Opin. Genet. Dev. Scholar). The can protein-protein and are a common pathological feature of paired helical aggregation and the conformation of phosphorylation also ability to with SUMO the between tau phosphorylation and were with tau and and with okadaic Treatment with phosphatase has to increase phosphorylation of tau at as by the T. J. PubMed Scopus Google not SUMO substrates were and tau sumoylation was by This that the conjugation of to tau was in to okadaic has that the of tau to microtubules is negatively regulated by phosphorylation G. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The okadaic sumoylation of tau suggests the that soluble tau may a target for tau and were with to of As in microtubule tau sumoylation. This the that from the the soluble pool of tau is free to with SUMO and undergo covalent Tau and α-synuclein belong to a family of natively unfolded proteins that secondary structure in the of a pathological proteins can also undergo that to protein aggregation and In the of tau and α-synuclein, their pathological in the formation of inclusions and Post-translational modifications are important of protein structure and Both tau and α-synuclein are subject to modifications as and ubiquitination. Sumoylation is the covalent attachment of SUMO proteins to target through an enzymatic pathway similar but distinct from SUMO modification is as an important post-translational modification protein-protein interactions, subcellular localization, and protein Although sumoylation has as a revealed that a of proteins is for SUMO modification E.S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, C. D. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In the have that the two natively unfolded proteins, tau and α-synuclein, are in Both proteins are to with little modification for the SUMO2 or SUMO3. In contrast to α-synuclein, which is the sumoylation of tau the conjugation of and SUMO analyses identified which within a SUMO consensus as a major for conjugation to The of a of target lysine is to conjugation of the ubiquitin-like at Yeh H.-L. Chen A. Li S. S.-L. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). 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In the the conjugation of to two natively unfolded proteins, tau and This modification pathway was in proteasome-mediated protein as as other functional modifications as phosphorylation. that both tau and α-synuclein define a number of neurodegenerative and the of SUMO conjugation in the of sumoylation in the of and α-synucleinopathies We Hay of for the SUMO expression Davies of for tau and for

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