Loss of KEAP1 Causes an Accumulation of Nondegradative Organelles

KEAP1 is a cytoplasmic protein that functions as an adaptor for the Cullin-3-based ubiquitin E3 ligase system, which regulates the degradation of many proteins, including NFE2L2/NRF2 and p62/SQSTM1. Loss of KEAP1 leads to an accumulation of protein ubiquitin aggregates and defective autophagy. To be...

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Published in:Antioxidants 2022-07, Vol.11 (7), p.1398
Main Authors: Uribe-Carretero, Elisabet, Martinez-Chacón, Guadalupe, Yakhine-Diop, Sokhna M. S., Duque-González, Gema, Rodríguez-Arribas, Mario, Alegre-Cortés, Eva, Paredes-Barquero, Marta, Canales-Cortés, Saray, Pizarro-Estrella, Elisa, Cuadrado, Antonio, González-Polo, Rosa Ana, Fuentes, José M., Niso-Santano, Mireia
Format: Article
Language:English
Subjects:
Antibodies
Autophagy
Biotechnology
Cathepsin D
Cullin
Embryo fibroblasts
Endosomes
Enzymes
Experiments
Fluorescence microscopy
Glycerol
Humidity
KEAP1
Laboratories
LAMP1
Lysosomes
Membranes
Organelles
Phagosomes
Proteins
Transcription factors
Ubiquitin
Ubiquitin-protein ligase
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Summary:KEAP1 is a cytoplasmic protein that functions as an adaptor for the Cullin-3-based ubiquitin E3 ligase system, which regulates the degradation of many proteins, including NFE2L2/NRF2 and p62/SQSTM1. Loss of KEAP1 leads to an accumulation of protein ubiquitin aggregates and defective autophagy. To better understand the role of KEAP1 in the degradation machinery, we investigated whether Keap1 deficiency affects the endosome-lysosomal pathway. We used KEAP1-deficient mouse embryonic fibroblasts (MEFs) and combined Western blot analysis and fluorescence microscopy with fluorometric and pulse chase assays to analyze the levels of lysosomal-endosomal proteins, lysosomal function, and autophagy activity. We found that the loss of keap1 downregulated the protein levels and activity of the cathepsin D enzyme. Moreover, KEAP1 deficiency caused lysosomal alterations accompanied by an accumulation of autophagosomes. Our study demonstrates that KEAP1 deficiency increases nondegradative lysosomes and identifies a new role for KEAP1 in lysosomal function that may have therapeutic implications.
ISSN:2076-3921
2076-3921
DOI:10.3390/antiox11071398