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 and Kamran Atabai ()
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Michael J. Podolsky: Weill Cornell Medical College
Benjamin Kheyfets: Weill Cornell Medical College
Monika Pandey: Weill Cornell Medical College
Afaq H. Beigh: Weill Cornell Medical College
Christopher D. Yang: University of California
Carlos O. Lizama: University of California
Ritwik Datta: University of California
Liangguang L. Lin: University of Virginia School of Medicine
Zhihong Wang: University of Virginia School of Medicine
Paul J. Wolters: University of California
Michael T. McManus: University of California
Ling Qi: University of Virginia School of Medicine
Kamran Atabai: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45817-8

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