Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover.
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 Information
Michael J Podolsky: Department of Medicine, Weill Cornell Medical College, New York, NY, USA. mip9227@med.cornell.edu. ORCID
Benjamin Kheyfets: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Monika Pandey: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Afaq H Beigh: Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Christopher D Yang: Cardiovascular Research Institute, University of California, San Francisco, CA, USA. ORCID
Carlos O Lizama: Cardiovascular Research Institute, University of California, San Francisco, CA, USA. ORCID
Ritwik Datta: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Liangguang L Lin: Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA. ORCID
Zhihong Wang: Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA. ORCID
Paul J Wolters: Department of Medicine, University of California, San Francisco, CA, USA. ORCID
Michael T McManus: Department of Microbiology and Immunology and UCSF Diabetes Center, University of California, San Francisco, CA, USA. ORCID
Ling Qi: Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA. ORCID
Kamran Atabai: Cardiovascular Research Institute, University of California, San Francisco, CA, USA. kamran.atabai@ucsf.edu. ORCID
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.
References
Protein Sci. 2001 Oct;10(10):2114-22
[PMID: 11567102]
