Academic Journal
A Golgi-bypass secretion mechanism for proTGFα involving TMED9 and GRASP65.
| Τίτλος: | A Golgi-bypass secretion mechanism for proTGFα involving TMED9 and GRASP65. |
|---|---|
| Συγγραφείς: | Steigleder SS; Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, 50931 Cologne, Germany., Döring I; Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, 50931 Cologne, Germany., Tauber M; Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, 50931 Cologne, Germany., Nüchel J; Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Lemberg MK; Center for Biochemistry and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany. |
| Πηγή: | Journal of cell science [J Cell Sci] 2026 Aug 15; Vol. 139 (16). Date of Electronic Publication: 2026 Aug 28. |
| Τύπος έκδοσης: | Journal Article; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Company of Biologists Country of Publication: England NLM ID: 0052457 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9137 (Electronic) Linking ISSN: 00219533 NLM ISO Abbreviation: J Cell Sci Subsets: MEDLINE |
| Imprint Name(s): | Publication: Cambridge : Company of Biologists Original Publication: London. |
| Ιατρικοί όροι (MeSH): | Golgi Apparatus*/metabolism , Membrane Proteins*/metabolism , Membrane Proteins*/genetics , Protein Precursors*/metabolism, Golgi Matrix Proteins/metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Protein Transport ; HeLa Cells ; Animals ; Autophagy |
| Περίληψη: | We recently demonstrated that the endoplasmic reticulum export of proTGFα (encoded by TGFA) is tightly gated and that proteostasis factors, including the intramembrane protease RHBDL4 (also known as RHBDD1), can promote its release by an unknown mechanism. While investigating a potential link between RHBDL4-regulated p24 (TMED) family proteins and proTGFα trafficking, we uncovered an RHBDL4-independent pathway in which the cargo receptor TMED9 induces unconventional protein secretion (UcPS) of ectopically expressed proTGFα. This pathway selectively requires GRASP65 (also known as GORASP1), but not the closely related GRASP55 (or GORASP2), and depends on components of the autophagic machinery and the ESCRT-associated protein ALIX (also known as PDCD6IP), consistent with a Golgi-bypass secretion route. TMED9- and GRASP65-induced proTGFα secretion is insensitive to brefeldin A treatment and involves trafficking through pre-Golgi compartments. Although largely based on overexpression systems, our findings identify a previously unrecognized UcPS mechanism and provide insight into alternative protein trafficking pathways that might be exploited under conditions of proteostasis stress and in pathological contexts such as cancer and inflammation. At present, our data establish the existence of a TMED9- and GRASP65-dependent Golgi-bypass trafficking route under conditions of ectopic cargo expression, whereas its endogenous physiological relevance remains to be established. (© 2026. Published by The Company of Biologists.) |
| Competing Interests: | Competing interests The authors declare no competing or financial interests. |
| Grant Information: | C10 Center for Molecular Medicine Cologne, University of Cologne; CAP31 Center for Molecular Medicine Cologne, University of Cologne; NU 467/1-1 Deutsche Forschungsgemeinschaft; NU 467/2-1 Deutsche Forschungsgemeinschaft; 28/2026 Köln Fortune |
| Contributed Indexing: | Keywords: GRASP65; Golgi-bypass trafficking; Proteostasis; Secretory autophagy; TMED9; Unconventional protein secretion |
| Substance Nomenclature: | 0 (Membrane Proteins) 0 (GORASP1 protein, human) 0 (Golgi Matrix Proteins) 0 (GORASP2 protein, human) 0 (Protein Precursors) |
| Entry Date(s): | Date Created: 20260727 Date Completed: 20260828 Latest Revision: 20260906 |
| Update Code: | 20260906 |
| DOI: | 10.1242/jcs.264719 |
| PMID: | 42504547 |
| Βάση Δεδομένων: | MEDLINE |
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