TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins
Abstract: 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.
- Location
-
Deutsche Nationalbibliothek Frankfurt am Main
- Extent
-
Online-Ressource
- Language
-
Englisch
- Bibliographic citation
-
TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins ; day:06 ; month:11 ; year:2023 ; extent:30
The EMBO journal / European Molecular Biology Organization ; (06.11.2023) (gesamt 30)
- Creator
-
Hayashi, Yuki
Takatori, Sho
Warsame, Waleed Y.
Tomita, Taisuke
Fujisawa, Takao
Ichijo, Hidenori
- DOI
-
10.15252/embj.2023114272
- URN
-
urn:nbn:de:101:1-2023110614294661042897
- Rights
-
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
-
14.08.2025, 10:58 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Hayashi, Yuki
- Takatori, Sho
- Warsame, Waleed Y.
- Tomita, Taisuke
- Fujisawa, Takao
- Ichijo, Hidenori
Other Objects (12)
Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome
A tunable LIC1-adaptor interaction modulates dynein activity in a cargo-specific manner
Chaperone-mediated autophagy in neuronal dendrites recruits cargo for local activity-dependent lysosomal release
An aberrant sugar modification of BACE 1 blocks its lysosomal targeting in A lzheimer's disease
Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency
Recognition of basic sorting motifs within synaptic membrane cargo proteins by the clathrin-adaptor complex AP-2
Souffle/Spastizin regulates secretory granule maturation by sorting lysosomal cargo from immature secretory granule during zebrafish oogenesis
cargo
Alpha 2-macroglobulin acts as a clearance factor in the lysosomal degradation of extracellular misfolded proteins
Proskar Anamorphic Adaptor Corona Cinemascope
MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease
Immune adaptor SKAP1 acts a scaffold for Polo-like kinase 1 (PLK1) for the optimal cell cycling of T-cells
Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome
A tunable LIC1-adaptor interaction modulates dynein activity in a cargo-specific manner
Chaperone-mediated autophagy in neuronal dendrites recruits cargo for local activity-dependent lysosomal release
An aberrant sugar modification of BACE 1 blocks its lysosomal targeting in A lzheimer's disease
Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency
Recognition of basic sorting motifs within synaptic membrane cargo proteins by the clathrin-adaptor complex AP-2
Souffle/Spastizin regulates secretory granule maturation by sorting lysosomal cargo from immature secretory granule during zebrafish oogenesis
cargo
Alpha 2-macroglobulin acts as a clearance factor in the lysosomal degradation of extracellular misfolded proteins
Proskar Anamorphic Adaptor Corona Cinemascope
MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease
Immune adaptor SKAP1 acts a scaffold for Polo-like kinase 1 (PLK1) for the optimal cell cycling of T-cells
Phosphoglycerate kinase 1 acts as a cargo adaptor to promote EGFR transport to the lysosome
A tunable LIC1-adaptor interaction modulates dynein activity in a cargo-specific manner
Chaperone-mediated autophagy in neuronal dendrites recruits cargo for local activity-dependent lysosomal release
An aberrant sugar modification of BACE 1 blocks its lysosomal targeting in A lzheimer's disease
Benzoxazole-derivatives enhance progranulin expression and reverse the aberrant lysosomal proteome caused by GRN haploinsufficiency
Recognition of basic sorting motifs within synaptic membrane cargo proteins by the clathrin-adaptor complex AP-2
Souffle/Spastizin regulates secretory granule maturation by sorting lysosomal cargo from immature secretory granule during zebrafish oogenesis
cargo
Alpha 2-macroglobulin acts as a clearance factor in the lysosomal degradation of extracellular misfolded proteins
Proskar Anamorphic Adaptor Corona Cinemascope
MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease