CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70

Makoto Urushitani, Junko Kurisu, Minako Tateno, Shigetsugu Hatakeyama, Keiichi Nakayama, Shinsuke Kato, Ryosuke Takahashi

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Over 100 mutants in superoxide dismutase 1 (SOD1) are reported in familial amyotrophic lateral sclerosis (ALS). However, the precise mechanism by which they are degraded through a ubiquitin-proteasomal pathway (UPP) remains unclear. Here, we report that heat-shock protein (Hsp) or heat-shock cognate (Hsc)70, and the carboxyl terminus of the Hsc70-interacting protein (CHIP), are involved in proteasomal degradation of mutant SOD1. Only mutant SOD1 interacted with Hsp/Hsc70 in vivo, and in vitro experiments revealed that Hsp/Hsc70 preferentially interacted with apo-SOD1 or dithiothreitol (DTT)-treated holo-SOD1, compared with metallated or oxidized forms. CHIP, a binding partner of Hsp/Hsc70, interacted only with mutant SOD1 and promoted its degradation. Both Hsp70 and CHIP promoted polyubiquitination of mutant SOD1-associated molecules, but not of mutant SOD1, indicating that mutant SOD1 is not a substrate of CHIP. Moreover, mutant SODl-associated Hsp/Hsc70, a known substrate of CHIP, was polyubiquitinated in vivo, and poly-ubiquitinated Hsc70 by CHIP interacted with the S5a subunit of the 26S proteasome in vitro. Furthermore, CHIP was predominantly expressed in spinal neurons, and ubiquitinated inclusions in the spinal motor neurons of hSOD1G93A transgenic mice were CHIP-immunoreactive. Taken together, we propose a novel pathway in which ubiquitinated Hsp/Hsc70 might deliver mutant SOD1 to, and facilitate its degradation, at the proteasome.

Original languageEnglish
Pages (from-to)231-244
Number of pages14
JournalJournal of Neurochemistry
Volume90
Issue number1
DOIs
Publication statusPublished - Jul 1 2004

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HSC70 Heat-Shock Proteins
Heat-Shock Proteins
Superoxide Dismutase
Degradation
Proteins
Neurons
Superoxide Dismutase-1
Amyotrophic lateral sclerosis 1
Ubiquitinated Proteins
Dithiothreitol
Motor Neurons
Proteasome Endopeptidase Complex
Substrates
Ubiquitin
Protein Binding
Transgenic Mice
Shock

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70. / Urushitani, Makoto; Kurisu, Junko; Tateno, Minako; Hatakeyama, Shigetsugu; Nakayama, Keiichi; Kato, Shinsuke; Takahashi, Ryosuke.

In: Journal of Neurochemistry, Vol. 90, No. 1, 01.07.2004, p. 231-244.

Research output: Contribution to journalArticle

Urushitani, Makoto ; Kurisu, Junko ; Tateno, Minako ; Hatakeyama, Shigetsugu ; Nakayama, Keiichi ; Kato, Shinsuke ; Takahashi, Ryosuke. / CHIP promotes proteasomal degradation of familial ALS-linked mutant SOD1 by ubiquitinating Hsp/Hsc70. In: Journal of Neurochemistry. 2004 ; Vol. 90, No. 1. pp. 231-244.
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AU - Nakayama, Keiichi

AU - Kato, Shinsuke

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