Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Abstract Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45817-8 |
| _version_ | 1797274136394858496 |
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| author | Michael J. Podolsky Benjamin Kheyfets Monika Pandey Afaq H. Beigh Christopher D. Yang Carlos O. Lizama Ritwik Datta Liangguang L. Lin Zhihong Wang Paul J. Wolters Michael T. McManus Ling Qi Kamran Atabai |
| author_facet | Michael J. Podolsky Benjamin Kheyfets Monika Pandey Afaq H. Beigh Christopher D. Yang Carlos O. Lizama Ritwik Datta Liangguang L. Lin Zhihong Wang Paul J. Wolters Michael T. McManus Ling Qi Kamran Atabai |
| author_sort | Michael J. Podolsky |
| collection | DOAJ |
| description | Abstract Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, here we execute unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discover a mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism appears to be dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of this protein. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus, we describe cell-autonomous, rheostatic collagen clearance as an important pathway of tissue homeostasis. |
| first_indexed | 2024-03-07T14:54:03Z |
| format | Article |
| id | doaj.art-f4c1e0221b354d99b77f1b6eea76ff85 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:54:03Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f4c1e0221b354d99b77f1b6eea76ff852024-03-05T19:32:21ZengNature PortfolioNature Communications2041-17232024-02-0115111710.1038/s41467-024-45817-8Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnoverMichael J. Podolsky0Benjamin Kheyfets1Monika Pandey2Afaq H. Beigh3Christopher D. Yang4Carlos O. Lizama5Ritwik Datta6Liangguang L. Lin7Zhihong Wang8Paul J. Wolters9Michael T. McManus10Ling Qi11Kamran Atabai12Department of Medicine, Weill Cornell Medical CollegeDepartment of Medicine, Weill Cornell Medical CollegeDepartment of Medicine, Weill Cornell Medical CollegeDepartment of Medicine, Weill Cornell Medical CollegeCardiovascular Research Institute, University of CaliforniaCardiovascular Research Institute, University of CaliforniaCardiovascular Research Institute, University of CaliforniaDepartment of Molecular Physiology and Biological Physics, University of Virginia School of MedicineDepartment of Molecular Physiology and Biological Physics, University of Virginia School of MedicineDepartment of Medicine, University of CaliforniaDepartment of Microbiology and Immunology and UCSF Diabetes Center, University of CaliforniaDepartment of Molecular Physiology and Biological Physics, University of Virginia School of MedicineCardiovascular Research Institute, University of CaliforniaAbstract Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors of ECM clearance, relatively little is understood regarding the upstream regulation of this process. Collagen is the most abundant constituent of normal and fibrotic ECM in mammalian tissues. Its catabolism occurs through extracellular proteolysis and cell-mediated uptake of collagen fragments for intracellular degradation. Given the paucity of information regarding the regulation of this latter process, here we execute unbiased genome-wide screens to understand the molecular underpinnings of cell-mediated collagen clearance. Using this approach, we discover a mechanism through which collagen biosynthesis is sensed by cells internally and directly regulates clearance of extracellular collagen. The sensing mechanism appears to be dependent on endoplasmic reticulum-resident protein SEL1L and occurs via a noncanonical function of this protein. This pathway functions as a homeostatic negative feedback loop that limits collagen accumulation in tissues. In human fibrotic lung disease, the induction of this collagen clearance pathway by collagen synthesis is impaired, thereby contributing to the pathological accumulation of collagen in lung tissue. Thus, we describe cell-autonomous, rheostatic collagen clearance as an important pathway of tissue homeostasis.https://doi.org/10.1038/s41467-024-45817-8 |
| spellingShingle | Michael J. Podolsky Benjamin Kheyfets Monika Pandey Afaq H. Beigh Christopher D. Yang Carlos O. Lizama Ritwik Datta Liangguang L. Lin Zhihong Wang Paul J. Wolters Michael T. McManus Ling Qi Kamran Atabai Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover Nature Communications |
| title | Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover |
| title_full | Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover |
| title_fullStr | Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover |
| title_full_unstemmed | Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover |
| title_short | Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover |
| title_sort | genome wide screens identify sel1l as an intracellular rheostat controlling collagen turnover |
| url | https://doi.org/10.1038/s41467-024-45817-8 |
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