Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover

• DOI: 10.1038/s41467-024-45817-8
• Publication Date: 2024-02-20T11:04:24Z
• Authors: 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
• Keywords: Homeostasis; Catabolism

Abstract Accumulating evidence has implicated impaired extracellular matrix (ECM) clearance as a key factor in fibrotic disease. Despite decades of research elucidating the effectors ECM clearance, relatively little is understood regarding upstream regulation this process. Collagen most abundant constituent normal and mammalian tissues. Its catabolism occurs through proteolysis cell-mediated uptake collagen fragments for intracellular degradation. Given paucity information latter process, here we execute unbiased genome-wide screens to understand molecular underpinnings clearance. Using approach, discover mechanism which biosynthesis sensed by cells internally directly regulates collagen. The sensing appears be dependent on endoplasmic reticulum-resident protein SEL1L via noncanonical function protein. This pathway functions homeostatic negative feedback loop that limits accumulation In human lung disease, induction synthesis impaired, thereby contributing pathological tissue. Thus, describe cell-autonomous, rheostatic an important tissue homeostasis.