RRC ID 79480
Author Kim HK, Jeong H, Jeong MG, Won HY, Lee G, Bae SH, Nam M, Lee SH, Hwang GS, Hwang ES.
Title TAZ deficiency impairs the autophagy-lysosomal pathway through NRF2 dysregulation and lysosomal dysfunction.
Journal Int J Biol Sci
Abstract Transcriptional coactivator with a PDZ-binding motif (TAZ) plays a key role in normal tissue homeostasis and tumorigenesis through interaction with several transcription factors. In particular, TAZ deficiency causes abnormal alveolarization and emphysema, and persistent TAZ overexpression contributes to lung cancer and pulmonary fibrosis, suggesting the possibility of a complex mechanism of TAZ function. Recent studies suggest that nuclear factor erythroid 2-related factor 2 (NRF2), an antioxidant defense system, induces TAZ expression during tumorigenesis and that TAZ also activates the NRF2-mediated antioxidant pathway. We thus thought to elucidate the cross-regulation of TAZ and NRF2 and the underlying molecular mechanisms and functions. TAZ directly interacted with NRF2 through the N-terminal domain and suppressed the transcriptional activity of NRF2 by preventing NRF2 from binding to DNA. In addition, the return of NRF2 to basal levels after signaling was inhibited in TAZ deficiency, resulting in sustained nuclear NRF2 levels and aberrantly increased expression of NRF2 targets. TAZ deficiency failed to modulate optimal NRF2 signaling and concomitantly impaired lysosomal acidification and lysosomal enzyme function, accumulating the abnormal autophagy vesicles and reactive oxygen species and causing protein oxidation and cellular damage in the lungs. TAZ restoration to TAZ deficiency normalized dysregulated NRF2 signaling and aberrant lysosomal function and triggered the normal autophagy-lysosomal pathway. Therefore, TAZ is indispensable for the optimal regulation of NRF2-mediated autophagy-lysosomal pathways and for preventing pulmonary damage caused by oxidative stress and oxidized proteins.
Volume 20(7)
Pages 2592-2606
Published 2024-1-1
DOI 10.7150/ijbs.88897
PII ijbsv20p2592
PMID 38725855
PMC PMC11077375
MeSH Adaptor Proteins, Signal Transducing Animals Autophagy* / physiology Humans Lysosomes* / metabolism Mice NF-E2-Related Factor 2* / metabolism Reactive Oxygen Species / metabolism Signal Transduction Transcription Factors / genetics Transcription Factors / metabolism Transcriptional Coactivator with PDZ-Binding Motif Proteins / metabolism
Mice RBRC01390