The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation

Pingzhao Zhang, Chenji Wang, Kun Gao, Dejie Wang, Jun Mao, Jian An, Chen Xu, Di Wu, Hongxiu Yu, Jun Liu, Long Yu

Research output: Contribution to journalArticle

Abstract

Thioredoxin interacting protein (TXNIP) was originally characterized as an endogenous inhibitor of thioredoxin, a key regulator in cellular redox homeostasis. TXNIP is also known to play important roles in tumor growth and metastasis, glucose and lipid metabolism. TXNIP expression is induced by various stress stimuli. However, it has been unclear how TXNIP is down-regulated. Here, we report that TXNIP undergoes proteasomal degradation in cells. We identify Itch as the E3 ubiquitin ligase for TXNIP. We demonstrate that Itch mediates polyubiquitination of TXNIP both in vitro and in vivo. Overexpression of Itch leads to TXNIP proteasomal degradation. Knockdown of Itch by small interfering RNA causes an accumulation of the steady-state level of TXNIP. We also show that the PPXY motifs of TXNIP and the WW domains of Itch mediate their interaction. Furthermore, the Itch-TXNIP interaction regulates intracellular reactive oxygen species levels and apoptosis. These findings establish a new mechanism for the negative regulation of TXNIP by Itch and shed new light on the regulation of cellular redox homeostasis.

Original languageEnglish (US)
Pages (from-to)8869-8879
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number12
DOIs
StatePublished - Mar 19 2010

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Thioredoxins
Ligases
Ubiquitin
Apoptosis
Degradation
Proteins
Oxidation-Reduction
Homeostasis
Ubiquitin-Protein Ligases
Lipid Metabolism
Small Interfering RNA
Proteolysis
Tumors
Reactive Oxygen Species

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation. / Zhang, Pingzhao; Wang, Chenji; Gao, Kun; Wang, Dejie; Mao, Jun; An, Jian; Xu, Chen; Wu, Di; Yu, Hongxiu; Liu, Jun; Yu, Long.

In: Journal of Biological Chemistry, Vol. 285, No. 12, 19.03.2010, p. 8869-8879.

Research output: Contribution to journalArticle

Zhang, Pingzhao ; Wang, Chenji ; Gao, Kun ; Wang, Dejie ; Mao, Jun ; An, Jian ; Xu, Chen ; Wu, Di ; Yu, Hongxiu ; Liu, Jun ; Yu, Long. / The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 12. pp. 8869-8879.
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AU - An, Jian

AU - Xu, Chen

AU - Wu, Di

AU - Yu, Hongxiu

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