| 1. |
- Hayashi, Yuki, et al.
(författare)
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TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins
- 2023
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Ingår i: EMBO Journal. - 0261-4189 .- 1460-2075. ; 41:23
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Tidskriftsartikel (refereegranskat)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 proteinTOLLIP 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.
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| 2. |
- Malinovschi, Andrei, 1978-, et al.
(författare)
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Clinical potential of eosinophil-derived neurotoxin in asthma management
- 2023
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 2213-2198 .- 2213-2201. ; 11:3, s. 750-761
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Tidskriftsartikel (refereegranskat)abstract
- The assessment and management of asthma patients is challenging because of the complexity of the underlying inflammatory mechanisms and heterogeneity of their clinical presentation. Optimizing disease management requires therapy individualization that should rely on reliable biomarkers to unravel the phenotypes and endotypes of asthma. The secretory activity and turnover of eosinophils, as assessed by measuring eosinophil-derived proteins, may provide an accurate and complementary tool that mirrors the eosinophil activation status. Emerging evidence suggests that eosinophil-derived neurotoxin (EDN) has considerable potential as a precision medicine biomarker. In this review, we explore EDN suitability as biomarker in asthma management, with particular emphasis on its clinical significance in the management of both pediatric and adult populations.
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