Proteolysis - Role of Parkin in the Ubiquitin-Proteasomal Pathway

Role of Parkin in the Ubiquitin-Proteasomal Pathway

Parkin is E3-ubiquitin-protein ligase that ubiquitinates itself and specific substrate proteins playing a protective role by sequestering misfolded proteins [1].

E3 ligases are part of the cellular machinery that tags proteins with ubiquitin, thereby targeting them for degradation by the proteasome. Ubiquitination of proteins occurs through sequential steps catalyzed by ubiquitin-activating (E1), conjugating (E2), and ligase (E3) enzymes.

In the case of Parkin, the ubiquitin-conjugating enzymes UBCH7 and UBCH8 are the participating E2s [2], [3], [4]. Additionally, Parkin interacts with endoplasmic-reticulum-associated E2s UBC6 and UBC7 [5].

Parkin has commonly been classified as a single-subunit E3 [6]. However, Parkin has been reported to interact with two known components of E3 ligase complexes, F-box and WD repeat domain containing 7 (FBXW7) and Cullin 1, which potentiate Parkin's ubiquitin ligase activity [7]. Furthermore, Parkin forms a complex with Heat shock protein 70 (HSP70) and STIP1 homology and U-box containing protein 1 (CHIP), enhancing its E3 enzymatic activity and its ability to inhibit cell death induced by unfolded protein stress [8].

One of the Parkin substrates is Septin 5 [4]. It is predominantly expressed in the nervous system, where it is associated with synaptic vesicles [9].

Parkin also ubiquitinates Tubulin alpha and Tubulin beta and increases their degradation. Microtubules are polymers of tubulin alpha/beta heterodimers. Misfolded tubulin monomers are highly toxic and quickly degraded [10].

Parkin associates with FBXW7 and Cullin 1 in the E3 ubiquitin ligase complex to ubiquitinate Cyclin E [7].

Synphilin 1 is an interaction partner of Alpha-synuclein involved in the formation of Lewy bodies under Parkinson's disease [11], [12], [13]. Parkin interacts with and ubiquitinates Synphilin 1 and promotes the ubiquitination of inclusion bodies [14].

The abundant unmodified form of Alpha-synuclein does not interact with Parkin [14]. Nevertheless a rare O-glycosylated form of Alpha-synuclein (alphaSp22) interacts with and is ubiquitinated by Parkin [15].

It was shown, that Synphilin 1 is ubiquitinated by other E3 ubiquitin-ligases, Seven in absentia homolog 1 and 2 (SIAH1 and SIAH2), promoting its degradation by the ubiquitin-proteasome system [16]. SIAH1 and SIAH2 facilitate Synphilin 1 degradation more efficiently than Parkin or another E3 ligase, Ring finger protein 19A (Dorfin) [16], [17], [18].

SIAH1 and SIAH2 also induce monoubiquitination of Alpha-synuclein that is not accompanied by proteasomal degradation of Alpha-synuclein, but rather, it promotes Alpha-synuclein aggregation and Lewy bodies' formation [16], [19], [20].

Parkin-associated endothelin receptor-like receptor (PAELR) is primarily expressed in oligodendrocytes, but also in a few distinct subpopulations of neurons. Unfolded and insoluble forms of PAELR can induce the selective degeneration of dopaminergic neurons. Parkin ubiquitinates this insoluble form of PAELR, promoting its degradation, which results in the suppression of unfolded-protein-induced cell death [5], [21], [22]. Under these conditions, Parkin apparently acts as part of the endoplasmic-reticulum-associated protein degradation machinery, utilizing the endoplasmic-reticulum-associated E2 enzymes, UBC6 and UBC7 [1]. CHIP, co-chaperone of HSP70, can enhance Parkin-mediated ubiquitination of PAELR [8], [22].

Caspase-1 and Caspase-8 cleave and inactivate cellular Parkin [23].

References:

1. von Coelln R, Dawson VL, Dawson TM
   Parkin-associated Parkinson's disease. Cell and tissue research 2004 Oct;318(1):175-84
2. Imai Y, Soda M, Takahashi R
   Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. The Journal of biological chemistry 2000 Nov 17;275(46):35661-4
3. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T
   Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature genetics 2000 Jul;25(3):302-5
4. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM
   Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proceedings of the National Academy of Sciences of the United States of America 2000 Nov 21;97(24):13354-9
5. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R
   An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001 Jun 29;105(7):891-902
6. Pickart CM
   Mechanisms underlying ubiquitination. Annual review of biochemistry 2001;70:503-33
7. Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A
   Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 2003 Mar 6;37(5):735-49
8. Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R
   CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Molecular cell 2002 Jul;10(1):55-67
9. Beites CL, Xie H, Bowser R, Trimble WS
   The septin CDCrel-1 binds syntaxin and inhibits exocytosis. Nature neuroscience 1999 May;2(5):434-9
10. Ren Y, Zhao J, Feng J
    Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. The Journal of neuroscience : the official journal of the Society for Neuroscience 2003 Apr 15;23(8):3316-24
11. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA
    Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nature genetics 1999 May;22(1):110-4
12. Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross CA, Takahashi H
    Synphilin-1 is present in Lewy bodies in Parkinson's disease. Annals of neurology 2000 Apr;47(4):521-3
13. Wakabayashi K, Engelender S, Tanaka Y, Yoshimoto M, Mori F, Tsuji S, Ross CA, Takahashi H
    Immunocytochemical localization of synphilin-1, an alpha-synuclein-associated protein, in neurodegenerative disorders. Acta neuropathologica 2002 Mar;103(3):209-14
14. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM
    Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature medicine 2001 Oct;7(10):1144-50
15. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, Mizuno Y, Kosik KS, Selkoe DJ
    Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease. Science (New York, N.Y.) 2001 Jul 13;293(5528):263-9
16. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S
    Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 2004 Apr 13;101(15):5500-5
17. Ito T, Niwa J, Hishikawa N, Ishigaki S, Doyu M, Sobue G
    Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. The Journal of biological chemistry 2003 Aug 1;278(31):29106-14
18. Nagano Y, Yamashita H, Takahashi T, Kishida S, Nakamura T, Iseki E, Hattori N, Mizuno Y, Kikuchi A, Matsumoto M
    Siah-1 facilitates ubiquitination and degradation of synphilin-1. The Journal of biological chemistry 2003 Dec 19;278(51):51504-14
19. Lee JT, Wheeler TC, Li L, Chin LS
    Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Human molecular genetics 2008 Mar 15;17(6):906-17
20. Rott R, Szargel R, Haskin J, Shani V, Shainskaya A, Manov I, Liani E, Avraham E, Engelender S
    Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. The Journal of biological chemistry 2008 Feb 8;283(6):3316-28
21. Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B
    Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 2003 Mar 27;37(6):911-24
22. Takahashi R, Imai Y
    Pael receptor, endoplasmic reticulum stress, and Parkinson's disease. Journal of neurology 2003 Oct;250 Suppl 3:III25-9
23. Kahns S, Kalai M, Jakobsen LD, Clark BF, Vandenabeele P, Jensen PH
    Caspase-1 and caspase-8 cleave and inactivate cellular parkin. The Journal of biological chemistry 2003 Jun 27;278(26):23376-80