The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation.
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.
Zhang
Pingzhao
P
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China.
Wang
Chenji
C
Gao
Kun
K
Wang
Dejie
D
Mao
Jun
J
An
Jian
J
Xu
Chen
C
Wu
Di
D
Yu
Hongxiu
H
Liu
Jun O
JO
Yu
Long
L
D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D025801:Ubiquitin / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D002352:Carrier Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C486715:TXNIP protein, human; D025801:Ubiquitin; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; D046988:Proteasome Endopeptidase Complex