Removal of hypersignaling endosomes by simaphagy.
| Title: | Removal of hypersignaling endosomes by simaphagy. |
|---|---|
| Authors: | Migliano SM; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Schultz SW; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Wenzel EM; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Takáts S; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Budapest, Hungary.; Liu D; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Mørk S; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Tan KW; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Medical Cell Biology, University of Uppsala, Uppsala, Sweden.; Rusten TE; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Raiborg C; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Stenmark H; Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. |
| Source: | Autophagy [Autophagy] 2024 Apr; Vol. 20 (4), pp. 769-791. Date of Electronic Publication: 2023 Oct 25. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101265188 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8635 (Electronic) Linking ISSN: 15548627 NLM ISO Abbreviation: Autophagy Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2015- : Philadelphia, PA : Taylor & Francis; Original Publication: Georgetown, TX : Landes Bioscience, 2005- |
| MeSH Terms: | Endosomes*/metabolism ; Endosomal Sorting Complexes Required for Transport*/metabolism ; Autophagy*/physiology ; Signal Transduction*; Intracellular Signaling Peptides and Proteins/metabolism ; Sequestosome-1 Protein/metabolism ; Autophagosomes/metabolism ; Endocytosis/physiology ; Humans ; Animals ; HeLa Cells ; Cell Movement |
| Abstract: | Activated transmembrane receptors continue to signal following endocytosis and are only silenced upon ESCRT-mediated internalization of the receptors into intralumenal vesicles (ILVs) of the endosomes. Accordingly, endosomes with dysfunctional receptor internalization into ILVs can cause sustained receptor signaling which has been implicated in cancer progression. Here, we describe a surveillance mechanism that allows cells to detect and clear physically intact endosomes with aberrant receptor accumulation and elevated signaling. Proximity biotinylation and proteomics analyses of ESCRT-0 defective endosomes revealed a strong enrichment of the ubiquitin-binding macroautophagy/autophagy receptors SQSTM1 and NBR1, a phenotype that was confirmed in cell culture and fly tissue. Live cell microscopy demonstrated that loss of the ESCRT-0 subunit HGS/HRS or the ESCRT-I subunit VPS37 led to high levels of ubiquitinated and phosphorylated receptors on endosomes. This was accompanied by dynamic recruitment of NBR1 and SQSTM1 as well as proteins involved in autophagy initiation and autophagosome biogenesis. Light microscopy and electron tomography revealed that endosomes with intact limiting membrane, but aberrant receptor downregulation were engulfed by phagophores. Inhibition of autophagy caused increased intra- and intercellular signaling and directed cell migration. We conclude that dysfunctional endosomes are surveyed and cleared by an autophagic process, simaphagy, which serves as a failsafe mechanism in signal termination.Abbreviations: AKT: AKT serine/threonine kinase; APEX2: apurinic/apyrimidinic endodoexyribonuclease 2; ctrl: control; EEA1: early endosome antigen 1; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; HGS/HRS: hepatocyte growth factor-regulated tyrosine kinase substrate; IF: immunofluorescence; ILV: intralumenal vesicle; KO: knockout; LIR: LC3-interacting region; LLOMe: L-leucyl-L-leucine methyl ester (hydrochloride); MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; NBR1: NBR1 autophagy cargo receptor; PAG10: Protein A-conjugated 10-nm gold; RB1CC1/FIP200: RB1 inducible coiled-coil 1; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TUB: Tubulin; UBA: ubiquitin-associated; ULK1: unc-51 like autophagy activating kinase 1; VCL: Vinculin; VPS37: VPS37 subunit of ESCRT-I; WB: western blot; WT: wild-type. |
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| Contributed Indexing: | Keywords: Autophagy; ESCRT; endosome; receptor degradation; signaling |
| Substance Nomenclature: | 0 (Endosomal Sorting Complexes Required for Transport); 0 (NBR1 protein, human); 0 (Intracellular Signaling Peptides and Proteins); 0 (Sequestosome-1 Protein); 0 (SQSTM1 protein, human) |
| Entry Date(s): | Date Created: 20231016 Date Completed: 20240429 Latest Revision: 20241010 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11062362 |
| DOI: | 10.1080/15548627.2023.2267958 |
| PMID: | 37840274 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't