UFMylation inhibits the proinflammatory capacity of interferon-γ-activated macrophages.

Autor:	Balce DR; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110; dbalce@vir.bio svirgin@vir.bio., Wang YT; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110.; Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., McAllaster MR; Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Dunlap BF; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Orvedahl A; Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Hykes BL Jr; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Droit L; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Handley SA; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Wilen CB; Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 06510.; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510., Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA 02142., Orchard RC; Department of Immunology and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Stallings CL; Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110., Virgin HW; Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110; dbalce@vir.bio svirgin@vir.bio.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Jan 05; Vol. 118 (1).
DOI:	10.1073/pnas.2011763118
Abstrakt:	Macrophages activated with interferon-γ (IFN-γ) in combination with other proinflammatory stimuli, such as lipopolysaccharide or tumor necrosis factor-α (TNF-α), respond with transcriptional and cellular changes that enhance clearance of intracellular pathogens at the risk of damaging tissues. IFN-γ effects must therefore be carefully balanced with inhibitory mechanisms to prevent immunopathology. We performed a genome-wide CRISPR knockout screen in a macrophage cell line to identify negative regulators of IFN-γ responses. We discovered an unexpected role of the ubiquitin-fold modifier (Ufm1) conjugation system (herein UFMylation) in inhibiting responses to IFN-γ and lipopolysaccharide. Enhanced IFN-γ activation in UFMylation-deficient cells resulted in increased transcriptional responses to IFN-γ in a manner dependent on endoplasmic reticulum stress responses involving Ern1 and Xbp1. Furthermore, UFMylation in myeloid cells is required for resistance to influenza infection in mice, indicating that this pathway modulates in vivo responses to infection. These findings provide a genetic roadmap for the regulation of responses to a key mediator of cellular immunity and identify a molecular link between the UFMylation pathway and immune responses. Competing Interests: Competing interest statement: D.R.B., M.R.M., and H.W.V. are now employed at Vir Biotechnology, but the initial findings reported here were made while at Washington University School of Medicine in St. Louis. The work at Washington University School of Medicine in St. Louis was not funded by Vir Biotechnology. J.G.D. consults for Agios, Foghorn Therapeutics, Maze Therapeutics, Merck, and Pfizer; J.G.D. consults for and has equity in Tango Therapeutics. J.G.D.’s interests were reviewed and are managed by the Broad Institute in accordance with its conflict of interest policies. H.W.V. is a founder of Casma Therapeutics, an autophagy-focused company. This paper has data relevant to autophagy, but the research in the paper was not funded by Casma. D.R.B., M.R.M., and H.W.V. are employees and hold stock in Vir Biotechnology, where some of the work was performed. H.W.V. is a founder of PierianDx, a genomic diagnostics company that did not fund the research in this report.
Databáze:	MEDLINE
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