Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP
Summary: Among its various functions, the sigma-1 receptor (σ1R) has been reported to modulate macroautophagy. It is currently unknown how this activity is mediated. We phylogenetically, structurally, and biochemically analyzed σ1R regarding its function in autophagy. We identified several putative...
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Elsevier
2025-09-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225015482 |
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| author | Marius Wilhelm Baeken Maximilian Christ Daniel Schmitt Wencke Trein Heike Nagel Albrecht Martin Clement Hagen Körschgen Christian Behl |
| author_facet | Marius Wilhelm Baeken Maximilian Christ Daniel Schmitt Wencke Trein Heike Nagel Albrecht Martin Clement Hagen Körschgen Christian Behl |
| author_sort | Marius Wilhelm Baeken |
| collection | DOAJ |
| description | Summary: Among its various functions, the sigma-1 receptor (σ1R) has been reported to modulate macroautophagy. It is currently unknown how this activity is mediated. We phylogenetically, structurally, and biochemically analyzed σ1R regarding its function in autophagy. We identified several putative LC3-interacting-regions (LIRs) that may mediate interactions with ATG8 proteins, which are known to promote autophagosome biogenesis, autophagic cargo reception, and lysosome fusion. Human σ1R comprises a LIR motif (hLIR5) typical for interaction with a specific ATG8, GABARAP. Biochemically, we uncovered a GABARAP-σ1R interaction depending on this motif via peptide array analysis and confirmed this via immunoprecipitation, co-localization, and proximity ligation assays. In addition, we verified a LIR-dependent presence of σ1R in isolated native autophagic vesicles. Excitingly, two point mutations within this LIR that have previously been reported to be associated with autosomal-recessive distal spinal muscular atrophy lack the ability to interact with GABARAP, highlighting the physiological relevance of the hLIR5-mediated σ1R-GABARAP interaction. |
| format | Article |
| id | doaj-art-4c3219c8ace440d09fb4676735edec66 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-4c3219c8ace440d09fb4676735edec662025-08-23T04:48:53ZengElsevieriScience2589-00422025-09-0128911328710.1016/j.isci.2025.113287Conserved LIR-specific interaction of Sigma-1 receptor and GABARAPMarius Wilhelm Baeken0Maximilian Christ1Daniel Schmitt2Wencke Trein3Heike Nagel4Albrecht Martin Clement5Hagen Körschgen6Christian Behl7Institute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanyInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanyInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanyInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanyInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanyInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanyInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, Germany; Corresponding authorInstitute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Duesbergweg 6, 55128 Mainz, GermanySummary: Among its various functions, the sigma-1 receptor (σ1R) has been reported to modulate macroautophagy. It is currently unknown how this activity is mediated. We phylogenetically, structurally, and biochemically analyzed σ1R regarding its function in autophagy. We identified several putative LC3-interacting-regions (LIRs) that may mediate interactions with ATG8 proteins, which are known to promote autophagosome biogenesis, autophagic cargo reception, and lysosome fusion. Human σ1R comprises a LIR motif (hLIR5) typical for interaction with a specific ATG8, GABARAP. Biochemically, we uncovered a GABARAP-σ1R interaction depending on this motif via peptide array analysis and confirmed this via immunoprecipitation, co-localization, and proximity ligation assays. In addition, we verified a LIR-dependent presence of σ1R in isolated native autophagic vesicles. Excitingly, two point mutations within this LIR that have previously been reported to be associated with autosomal-recessive distal spinal muscular atrophy lack the ability to interact with GABARAP, highlighting the physiological relevance of the hLIR5-mediated σ1R-GABARAP interaction.http://www.sciencedirect.com/science/article/pii/S2589004225015482BiochemistryMolecular biology |
| spellingShingle | Marius Wilhelm Baeken Maximilian Christ Daniel Schmitt Wencke Trein Heike Nagel Albrecht Martin Clement Hagen Körschgen Christian Behl Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP iScience Biochemistry Molecular biology |
| title | Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP |
| title_full | Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP |
| title_fullStr | Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP |
| title_full_unstemmed | Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP |
| title_short | Conserved LIR-specific interaction of Sigma-1 receptor and GABARAP |
| title_sort | conserved lir specific interaction of sigma 1 receptor and gabarap |
| topic | Biochemistry Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225015482 |
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