Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response
STING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING d...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717317138 |
| _version_ | 1811267314025234432 |
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| author | Vijay K. Gonugunta Tomomi Sakai Vladislav Pokatayev Kun Yang Jianjun Wu Nicole Dobbs Nan Yan |
| author_facet | Vijay K. Gonugunta Tomomi Sakai Vladislav Pokatayev Kun Yang Jianjun Wu Nicole Dobbs Nan Yan |
| author_sort | Vijay K. Gonugunta |
| collection | DOAJ |
| description | STING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER exit and function of vacuolar ATPase complex. Late-stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix amino acid 281 (aa281)–297 as a motif required for trafficking-mediated STING degradation. Immuno-electron microscopy (EM) reveals the size and clustering of STING vesicles and topology of STING on the vesicle. Importantly, blockade of trafficking-mediated STING degradation using bafilomycin A1 specifically enhanced cyclic guanosine monophosphate (GMP)-AMP (cGAMP)-mediated immune response and anti-tumor effect in mice. Together, our findings provide biochemical and imaging evidence for STING degradation by the lysosome and pinpoint trafficking-mediated STING degradation as a previously unanticipated therapeutic target for enhancing STING signaling in cancer therapy. |
| first_indexed | 2024-04-12T21:00:26Z |
| format | Article |
| id | doaj.art-6fb2ae1df4924b1f85f0c536b0840d36 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-12T21:00:26Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-6fb2ae1df4924b1f85f0c536b0840d362022-12-22T03:16:52ZengElsevierCell Reports2211-12472017-12-0121113234324210.1016/j.celrep.2017.11.061Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor ResponseVijay K. Gonugunta0Tomomi Sakai1Vladislav Pokatayev2Kun Yang3Jianjun Wu4Nicole Dobbs5Nan Yan6Department of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Immunology and Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USASTING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER exit and function of vacuolar ATPase complex. Late-stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix amino acid 281 (aa281)–297 as a motif required for trafficking-mediated STING degradation. Immuno-electron microscopy (EM) reveals the size and clustering of STING vesicles and topology of STING on the vesicle. Importantly, blockade of trafficking-mediated STING degradation using bafilomycin A1 specifically enhanced cyclic guanosine monophosphate (GMP)-AMP (cGAMP)-mediated immune response and anti-tumor effect in mice. Together, our findings provide biochemical and imaging evidence for STING degradation by the lysosome and pinpoint trafficking-mediated STING degradation as a previously unanticipated therapeutic target for enhancing STING signaling in cancer therapy.http://www.sciencedirect.com/science/article/pii/S2211124717317138STING degradationlysosomesanti-tumor response |
| spellingShingle | Vijay K. Gonugunta Tomomi Sakai Vladislav Pokatayev Kun Yang Jianjun Wu Nicole Dobbs Nan Yan Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response Cell Reports STING degradation lysosomes anti-tumor response |
| title | Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response |
| title_full | Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response |
| title_fullStr | Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response |
| title_full_unstemmed | Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response |
| title_short | Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response |
| title_sort | trafficking mediated sting degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti tumor response |
| topic | STING degradation lysosomes anti-tumor response |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717317138 |
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