Phosphorylation of CHIP at Ser20 by Cdk5 Promotes TAIF-mediated Neuronal Death

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2015 Jul 25

PMID 26206088

Citations 18

Authors

C Kim

N Yun

J Lee

M B H Youdim

C Ju

W-K Kim

P-L Han

Y J Oh

Affiliations

Soon will be listed here.

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIP-mediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP(S20A), but not CHIP(WT), attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.

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References

Skowyra D, Craig K, Tyers M, Elledge S, Harper J . F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997; 91(2):209-19. DOI: 10.1016/s0092-8674(00)80403-1. View

Gong X, Tang X, Wiedmann M, Wang X, Peng J, Zheng D . Cdk5-mediated inhibition of the protective effects of transcription factor MEF2 in neurotoxicity-induced apoptosis. Neuron. 2003; 38(1):33-46. DOI: 10.1016/s0896-6273(03)00191-0. View

Ballinger C, Connell P, Wu Y, Hu Z, Thompson L, Yin L . Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol. 1999; 19(6):4535-45. PMC: 104411. DOI: 10.1128/MCB.19.6.4535. View

Cheung E, Melanson-Drapeau L, Cregan S, Vanderluit J, Ferguson K, McIntosh W . Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J Neurosci. 2005; 25(6):1324-34. PMC: 6726004. DOI: 10.1523/JNEUROSCI.4261-04.2005. View

Shin Y, Klucken J, Patterson C, Hyman B, McLean P . The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J Biol Chem. 2005; 280(25):23727-34. DOI: 10.1074/jbc.M503326200. View

Sahara N, Murayama M, Mizoroki T, Urushitani M, Imai Y, Takahashi R . In vivo evidence of CHIP up-regulation attenuating tau aggregation. J Neurochem. 2005; 94(5):1254-63. DOI: 10.1111/j.1471-4159.2005.03272.x. View

Yuste V, Sanchez-Lopez I, Sole C, Moubarak R, Bayascas J, Dolcet X . The contribution of apoptosis-inducing factor, caspase-activated DNase, and inhibitor of caspase-activated DNase to the nuclear phenotype and DNA degradation during apoptosis. J Biol Chem. 2005; 280(42):35670-83. DOI: 10.1074/jbc.M504015200. View

Murata S, Minami M, Minami Y . Purification and assay of the chaperone-dependent ubiquitin ligase of the carboxyl terminus of Hsc70-interacting protein. Methods Enzymol. 2005; 398:271-9. DOI: 10.1016/S0076-6879(05)98022-1. View

Yang C, Zhou W, Jeon M, Demydenko D, Harada Y, Zhou H . Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell. 2006; 21(1):135-41. DOI: 10.1016/j.molcel.2005.11.014. View

10.

Qian S, McDonough H, Boellmann F, Cyr D, Patterson C . CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature. 2006; 440(7083):551-5. PMC: 4112096. DOI: 10.1038/nature04600. View

11.

Cheung Z, Fu A, Ip N . Synaptic roles of Cdk5: implications in higher cognitive functions and neurodegenerative diseases. Neuron. 2006; 50(1):13-8. DOI: 10.1016/j.neuron.2006.02.024. View

12.

Al-Ramahi I, Lam Y, Chen H, de Gouyon B, Zhang M, Perez A . CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J Biol Chem. 2006; 281(36):26714-24. DOI: 10.1074/jbc.M601603200. View

13.

Camins A, Verdaguer E, Folch J, Pallas M . Involvement of calpain activation in neurodegenerative processes. CNS Drug Rev. 2006; 12(2):135-48. PMC: 6494133. DOI: 10.1111/j.1527-3458.2006.00135.x. View

14.

Dickey C, Patterson C, Dickson D, Petrucelli L . Brain CHIP: removing the culprits in neurodegenerative disease. Trends Mol Med. 2006; 13(1):32-8. DOI: 10.1016/j.molmed.2006.11.003. View

15.

Jackson-Lewis V, Przedborski S . Protocol for the MPTP mouse model of Parkinson's disease. Nat Protoc. 2007; 2(1):141-51. DOI: 10.1038/nprot.2006.342. View

16.

Kumar P, Ambasta R, Veereshwarayya V, Rosen K, Kosik K, Band H . CHIP and HSPs interact with beta-APP in a proteasome-dependent manner and influence Abeta metabolism. Hum Mol Genet. 2007; 16(7):848-64. DOI: 10.1093/hmg/ddm030. View

17.

Avraham E, Rott R, Liani E, Szargel R, Engelender S . Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J Biol Chem. 2007; 282(17):12842-50. DOI: 10.1074/jbc.M608243200. View

18.

Hao B, Oehlmann S, Sowa M, Harper J, Pavletich N . Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. Mol Cell. 2007; 26(1):131-43. DOI: 10.1016/j.molcel.2007.02.022. View

19.

Ko H, Bailey R, Smith W, Liu Z, Shin J, Lee Y . CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc Natl Acad Sci U S A. 2009; 106(8):2897-902. PMC: 2650345. DOI: 10.1073/pnas.0810123106. View

20.

Son Y, Jang Y, Heo J, Chung W, Choi K, Lee J . Apoptosis-inducing factor plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. Apoptosis. 2009; 14(6):796-808. DOI: 10.1007/s10495-009-0353-7. View