Interaction Between DUSP8 and the Polyglutamine Protein Ataxin-1

Abstract

Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of polyQ repeats in the disease proteins. Expansion of polyQ repeats presumably leads to misfolding and aggregation of polyQ proteins.1 Although details of the molecular mechanisms are still elusive, transcriptional dysfunction and oxidative damage are suggested as underlying events responsible for polyQ pathogenesis.2 Misfolded polyQ proteins are frequently concentrated into intranuclear inclusions, which increase generation of reactive oxygen species (ROS) and activate stress signaling pathways. In cultured cells expressing expanded polyQ proteins, mitogen-activated protein kinases (MAPK), e.g., p38 and JNK, are activated and the cytotoxicity induced by polyQ proteins, partially through sustained activation of MAP kinases, can be reduced by administration of a p38 inhibitor.3-6 MAPK are activated by MAPK kinase (MEK)-mediated phosphorylation of threonine and tyrosine residues located in the signature sequence (TxY) and MEK is in turn activated by MAPK kinase kinase (MEKK).7 Since MAPK are involved in a wide variety of cellular processes including cell survival and apoptosis, cells must tightly regulate the magnitude and duration of MAPK activation. The negative regulation of MAPK is often achieved by phosphatase-mediated dephosphorylation of MAPK. A group of protein phosphatases referred as type I cysteinebased protein tyrosine phosphatases including DUSPs (dualspecificity phosphatases) dephosphorylate both tyrosine and serine/threonine residues within the same substrate and as a result counteract MAPK. 8Involvement of protein tyrosine phosphatases (PTPs) in polyQ-induced cell death has been reported in previous studies. Several PTP proteins including MKP-1 are up-regulated by over-expression of cytotoxic polyQ-expanded huntingtin (Htt) fragment.9 Moreover, polyQ-expanded Htt fragment activates JNK pathway by reducing solubility of JNK phosphatase M3/6 (also known as hVH5 or DUSP8). 4A recent study demonstrated that a DUSP protein laforin can suppress the cytotoxicity caused by misfolded proteins and hinted that phosphatases can be potential targets for pharmacological intervention of neurodegenerative disorders.10 The polyQ protein ataxin-1 is a soluble protein of about 816 amino acids, which varies depending on the length of polyQ repeats, and located both in the cytoplasm and nucleus. Although the exact functions are not completely understood, ataxin-1 is apparently involved in transcription regulation through its ability to interact with several transcription factors as well as RNA.11 While it is generally assumed that expansion of polyQ repeats causes misfolding of ataxin-1 and leads to neuronal death in spinocerebellar ataxia 1 (SCA1), contribution of other domains to pathogenesis also becomes increasingly clear. Besides N-terminal polyQ region, AXH domain (570-689; for interaction with transcription factors and RNA), endogenous phosphorylation site (776) and nuclear localization signal (795-798) a...