Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal

• 成果类型: Article
• 署名作者: Banuelos, Allison; Baez, Michelle; Zhang, Allison; Yilmaz, Leyla; Kasberg, William; Volk, Regan; Georgeos, Nardin; Sedova, Elle Koren -; Le, Uyen; Burden, Andrew T.; Marjon, Kristopher D.; Schwartz, Jennifer Lippincott -; Zaro, Balyn W.; Weissman, Irving L.
• 署名单位: Stanford University; Stanford University; Howard Hughes Medical Institute; University of California System; University of California San Francisco; Stanford University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11956
• DOI: 10.1073/pnas.2426644122
• 发表日期: 2025-05-27
• 关键词: endoplasmic-reticulum; surface calreticulin; apoptotic cells; protein; engagement; phagocytosis; expression; clearance; exposure; cd91

摘要

Calreticulin (CALR) is primarily an endoplasmic reticulum chaperone protein that also plays a key role in facilitating programmed cell removal (PrCR) by acting as an eat-me signal for macrophages, directing their recognition and engulfment of dying, diseased, or unwanted cells. Recent findings have demonstrated that macrophages can transfer their own CALR onto exposed asialoglycans on target cells, marking them for PrCR. Despite the critical role CALR plays in this process, the molecular mechanisms behind its secretion by macrophages and the formation of binding sites on target cells remain unclear. Our findings show that CALR undergoes C-terminal cleavage upon secretion, producing a truncated form that functions as the active eat-me signal detectable on target cells. We identify cathepsins as potential proteases involved in this cleavage process. Furthermore, we demonstrate that macrophages release neuraminidases, which modify the surface of target cells and facilitate CALR binding. These insights reveal a coordinated mechanism through which lipopolysaccharide (LPS)-activated macrophages regulate CALR cleavage and neuraminidase activity to mark target cells for PrCR. How they recognize the cells to be targeted remains unknown.