Regulation of lysosome integrity and lysophagy by the ubiquitin-conjugating enzyme UBE2QL1.
Bojana KravicChristian BehrendsHemmo MeyerPublished in: Autophagy (2019)
Lysosomal membrane permeabilization or full rupture of lysosomes is a common and severe stress condition that is relevant for degenerative disease, infection and cancer. Cells respond with extensive ubiquitination of damaged lysosomes, which triggers selective macroautophagy/autophagy of the whole organelle, termed lysophagy. We screened an siRNA library targeting human E2-conjugating enzymes and identified UBE2QL1 as critical for efficient lysosome ubiquitination after chemically-induced lysosomal damage. UBE2QL1 translocates to lysosomes upon damage and associates with autophagy regulators. Loss of UBE2QL1-mediated ubiquitination reduces association of the autophagy receptor SQSTM1/p62 and the LC3-decorated phagophore, and prevents recruitment of the ubiquitin-targeted AAA-ATPase VCP/p97 that facilitates lysophagy. Even in unchallenged cells, UBE2QL1 depletion leads to MTOR dissociation and TFEB activation, and mutation of the homolog UBC-25 destabilizes lysosomes in C. elegans, indicating that UBE2QL1 is critical for maintaining lysosome integrity in addition to lysophagy.
Keyphrases
- oxidative stress
- endoplasmic reticulum stress
- cell death
- induced apoptosis
- signaling pathway
- cancer therapy
- fluorescent probe
- endothelial cells
- living cells
- small molecule
- diabetic rats
- cell cycle arrest
- cell proliferation
- high glucose
- quantum dots
- drug delivery
- mouse model
- drug induced
- simultaneous determination
- pi k akt
- pluripotent stem cells