Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection
AuthorsNhan, James D.
Turner, Christian D.
Anderson, Sarah M.
Dalton, Hans M.
Cheesman, Hilary K.
Ruter, Dana L.
Uma Naresh, Nandhitha
Haynes, Cole M.
Soukas, Alexander A.
Curran, Sean P.
UMass Chan AffiliationsDepartment of Molecular, Cell and Cancer Biology
Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine
Document TypeJournal Article
Amino Acids, Peptides, and Proteins
Bacterial Infections and Mycoses
Biochemical Phenomena, Metabolism, and Nutrition
Hemic and Immune Systems
Immunology and Infectious Disease
MetadataShow full item record
AbstractEarly host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1-dependent loss of somatic fat. These data define a SKN-1- and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.
Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22322-22330. doi: 10.1073/pnas.1909666116. Epub 2019 Oct 14. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/41241
RightsCopyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Except where otherwise noted, this item's license is described as Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).