@article{c3800e1ffd5a465b82a1f6aa04c2408b,
title = "UFMylation inhibits the proinflammatory capacity of interferon-γ–activated macrophages",
abstract = "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.",
keywords = "Autophagy, ER stress, Immunology, Interferon, UFMylation",
author = "Balce, {Dale R.} and Wang, {Ya Ting} and McAllaster, {Michael R.} and Dunlap, {Bria F.} and Anthony Orvedahl and Hykes, {Barry L.} and Lindsay Droit and Handley, {Scott A.} and Wilen, {Craig B.} and Doench, {John G.} and Orchard, {Robert C.} and Stallings, {Christina L.} and Virgin, {Herbert W.}",
note = "Funding Information: 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.{\textquoteright}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. Published under the PNAS license. 1Present address: Vir Biotechnology, San Francisco, CA 94158. 2To whom correspondence may be addressed. Email: dbalce@vir.bio or svirgin@vir.bio. This article contains supporting information online at https://www.pnas.org/lookup/suppl/ doi:10.1073/pnas.2011763118/-/DCSupplemental. Published December 28, 2020. Funding Information: ACKNOWLEDGMENTS. We thank the Genetic Perturbation Platform at the Broad Institute of MIT and Harvard for technical support; multiple resources and people at the Washington University School of Medicine in St. Louis, including Darren Kreamalmeyer, Monica Sentmanat at the Genome Engineering and IPSC Center, the Genome Technology Access Center, the Flow Cytometry & Fluorescence Activated Cell Sorting Core Facility; Wandy L. Beatty at the Molecular Microbiology Imaging Facility; and the Edison Family Center for Genome Sciences & Systems Biology. This work was supported by NIH Grants U19 AI109725 (to H.W.V.), R00 DK116666 (to R.C.O.), U19 AI142784 (to H.W.V. and C.L.S.), R01 AI132697 (to C.L.S.); and a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award (to C.L.S.). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = jan,
day = "5",
doi = "10.1073/PNAS.2011763118",
language = "English",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "1",
}