Macrophages release neuraminidase and cleaved calreticulin for programmed cell removal
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Allison Banuelos
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Michelle Baez
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Allison Zhang
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Leyla Yılmaz
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
William Kasberg
Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin
Regan Volk
Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California
Nardin Georgeos
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Elle Koren-Sedova
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Uyen Le
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Andrew T. Burden
Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University
Kristopher D. Marjon
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
Jennifer Lippincott-Schwartz
Balyn W. Zaro
Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California
Irving L. Weissman