TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.
ER-phagy
TOLLIP
cargo adaptor
intrinsically disordered region
lysosome
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
revised:
10
10
2023
received:
17
04
2023
accepted:
11
10
2023
medline:
4
12
2023
pubmed:
6
11
2023
entrez:
6
11
2023
Statut:
ppublish
Résumé
Endoplasmic reticulum (ER) proteostasis is maintained by various catabolic pathways. Lysosomes clear entire ER portions by ER-phagy, while proteasomes selectively clear misfolded or surplus aberrant proteins by ER-associated degradation (ERAD). Recently, lysosomes have also been implicated in the selective clearance of aberrant ER proteins, but the molecular basis remains unclear. Here, we show that the phosphatidylinositol-3-phosphate (PI3P)-binding protein TOLLIP promotes selective lysosomal degradation of aberrant membrane proteins, including an artificial substrate and motoneuron disease-causing mutants of VAPB and Seipin. These cargos are recognized by TOLLIP through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain. In contrast to ER-phagy receptors, which clear both native and aberrant proteins by ER-phagy, TOLLIP selectively clears aberrant cargos by coupling them with the PI3P-dependent lysosomal trafficking without promoting bulk ER turnover. Moreover, TOLLIP depletion augments ER stress after ERAD inhibition, indicating that TOLLIP and ERAD cooperatively safeguard ER proteostasis. Our study identifies TOLLIP as a unique type of cargo-specific adaptor dedicated to the clearance of aberrant ER cargos and provides insights into molecular mechanisms underlying lysosome-mediated quality control of membrane proteins.
Identifiants
pubmed: 37929762
doi: 10.15252/embj.2023114272
pmc: PMC10690474
doi:
Substances chimiques
Membrane Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e114272Subventions
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP21gm5010001
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP21K15026
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP23K14143
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP22K06610
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP21H04760
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP22H04636
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP22H04804
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : JP23H00394
Organisme : MEXT | JST | Moonshot Research and Development Program (Moonshot)
ID : JPMJMS2022-18
Organisme : MEXT | JST | Moonshot Research and Development Program (Moonshot)
ID : JPMJMS2024
Organisme : SERIKA FUND
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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