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The ubiquitin‐conjugating enzyme UBE 2 QL 1 coordinates lysophagy in response to endolysosomal damage
Author(s) -
Koerver Lisa,
Papadopoulos Chrisovalantis,
Liu Bin,
Kravic Bojana,
Rota Giulia,
Brecht Lukas,
Veenendaal Tineke,
Polajnar Mira,
Bluemke Anika,
Ehrmann Michael,
Klumperman Judith,
Jäättelä Marja,
Behrends Christian,
Meyer Hemmo
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948014
Subject(s) - enzyme , ubiquitin , microbiology and biotechnology , chemistry , biochemistry , biology , gene
The autophagic clearance of damaged lysosomes by lysophagy involves extensive modification of the organelle with ubiquitin, but the underlying ubiquitination machinery is still poorly characterized. Here, we use an si RNA screening approach and identify human UBE 2 QL 1 as a major regulator of lysosomal ubiquitination, lysophagy, and cell survival after lysosomal damage. UBE 2 QL 1 translocates to permeabilized lysosomes where it associates with damage sensors, ubiquitination targets, and lysophagy effectors. UBE 2 QL 1 knockdown reduces ubiquitination and accumulation of the critical autophagy receptor p62 and abrogates recruitment of the AAA ‐ ATP ase VCP /p97, which is essential for efficient lysophagy. Crucially, it affects association of LC 3B with damaged lysosomes indicating that autophagosome formation was impaired. Already in unchallenged cells, depletion of UBE 2 QL 1 leads to increased lysosomal damage, mTOR dissociation from lysosomes, and TFEB activation pointing to a role in lysosomal homeostasis. In line with this, mutation of the homologue ubc‐25 in Caenorhabditis elegans exacerbates lysosome permeability in worms lacking the lysosome stabilizing protein SCAV ‐3/ LIMP 2. Thus, UBE 2 QL 1 coordinates critical steps in the acute endolysosomal damage response and is essential for maintenance of lysosomal integrity.