HECT-Type Ubiquitin E3 Ligase ITCH Interacts With Thioredoxin-Interacting Protein and Ameliorates Reactive Oxygen Species-Induced Cardiotoxicity

Journal of the American Heart Association
Yoichiro OtakiIsao Kubota

Abstract

The homologous to the E6-AP carboxyl terminus (HECT)-type ubiquitin E3 ligase ITCH is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin-interacting protein (TXNIP) is a negative regulator of the thioredoxin system and an endogenous reactive oxygen species scavenger. In the present study, we focused on the functional role of ubiquitin E3 ligase ITCH and its interaction with TXNIP to elucidate the mechanism of cardiotoxicity induced by reactive oxygen species, such as doxorubicin and hydrogen peroxide. Protein interaction between TXNIP and ITCH in cardiomyocyte was confirmed by immunoprecipitation assays. Overexpression of ITCH increased proteasomal TXNIP degradation and augmented thioredoxin activity, leading to inhibition of reactive oxygen species generation, p38 MAPK, p53, and subsequent intrinsic pathway cardiomyocyte apoptosis in reactive oxygen species-induced cardiotoxicity. Conversely, knockdown of ITCH using small interfering RNA inhibited TXNIP degradation and resulted in a subsequent increase in cardiomyocyte apoptosis. Next, we generated a transgenic mouse with cardiac-specific overexpression of ITCH, called the ITCH-Tg mouse. The expressio...Continue Reading

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Citations

Feb 10, 2017·The Journal of Physiology·Jennifer E Gilda, Aldrin V Gomes
Oct 20, 2019·Cell Cycle·Wen-Cai ZhangLuo-Sha Zhao
Feb 11, 2020·PloS One·Ken WatanabeMasafumi Watanabe
Jun 27, 2020·Scientific Reports·Daisuke KinoshitaMasafumi Watanabe
Jul 20, 2019·The Journal of Biological Chemistry·Zachary T KelleherHarvey E Marshall
Feb 12, 2021·International Journal of Molecular Sciences·Alison DominguesValérie Nivet-Antoine
Mar 14, 2020·Seminars in Cancer Biology·Qing YinLixin Wan
Sep 29, 2020·Journal of Translational Internal Medicine·Hao QianYingxian Sun
Jun 10, 2021·Laboratory Investigation; a Journal of Technical Methods and Pathology·Qian-Qian ZhuHong-Kun Zhang
Jul 3, 2021·International Journal of Molecular Sciences·Jun GotoMasafumi Watanabe

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Methods Mentioned

BETA
transgenic
PCR
Assay
Scanning Electron Microscopy
immunoprecipitation
reverse transcription PCR
transmission electron microscopy

Software Mentioned

SAS
JMP
ImageJ

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