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Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis

NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that NADPH oxidase suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammato...

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Autores principales: Gordon, Rachael A., Giannouli, Christina, Raparia, Chirag, Bastacky, Sheldon I., Marinov, Anthony, Hawse, William, Cattley, Richard, Tilstra, Jeremy S., Campbell, Allison M., Nickerson, Kevin M., Davidson, Anne, Shlomchik, Mark J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057630/
https://www.ncbi.nlm.nih.gov/pubmed/35192551
http://dx.doi.org/10.1172/jci.insight.155537
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author Gordon, Rachael A.
Giannouli, Christina
Raparia, Chirag
Bastacky, Sheldon I.
Marinov, Anthony
Hawse, William
Cattley, Richard
Tilstra, Jeremy S.
Campbell, Allison M.
Nickerson, Kevin M.
Davidson, Anne
Shlomchik, Mark J.
author_facet Gordon, Rachael A.
Giannouli, Christina
Raparia, Chirag
Bastacky, Sheldon I.
Marinov, Anthony
Hawse, William
Cattley, Richard
Tilstra, Jeremy S.
Campbell, Allison M.
Nickerson, Kevin M.
Davidson, Anne
Shlomchik, Mark J.
author_sort Gordon, Rachael A.
collection PubMed
description NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that NADPH oxidase suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammatory syndrome in aged, nonautoimmune mice. Prior work implicated cytochrome b-245, β polypeptide (CYBB), a component of the NADPH oxidase complex, and the RUN and cysteine-rich domain-containing Beclin 1–interacting protein (RUBICON) as requisite for LAP. To test the hypothesis that NADPH oxidase deficiency exacerbates lupus via a defect in LAP, we deleted Rubicon in the B6.Sle1.Yaa and MRL.Fas(lpr) lupus mouse models. Under this hypothesis, RUBICON deficiency should phenocopy NADPH oxidase deficiency, as both work in the same pathway. However, we observed the opposite — RUBICON deficiency resulted in reduced mortality, renal disease, and autoantibody titers to RNA-associated autoantigens. Given that our data contradict the published role for LAP in autoimmunity, we assessed whether CYBB and RUBICON are requisite for LAP. We found that LAP is not dependent on either of these 2 pathways. To our knowledge, our data reveal RUBICON as a novel regulator of SLE, possibly by a B cell–intrinsic mechanism, but do not support a role for LAP in lupus.
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spelling pubmed-90576302022-05-04 Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis Gordon, Rachael A. Giannouli, Christina Raparia, Chirag Bastacky, Sheldon I. Marinov, Anthony Hawse, William Cattley, Richard Tilstra, Jeremy S. Campbell, Allison M. Nickerson, Kevin M. Davidson, Anne Shlomchik, Mark J. JCI Insight Research Article NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that NADPH oxidase suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammatory syndrome in aged, nonautoimmune mice. Prior work implicated cytochrome b-245, β polypeptide (CYBB), a component of the NADPH oxidase complex, and the RUN and cysteine-rich domain-containing Beclin 1–interacting protein (RUBICON) as requisite for LAP. To test the hypothesis that NADPH oxidase deficiency exacerbates lupus via a defect in LAP, we deleted Rubicon in the B6.Sle1.Yaa and MRL.Fas(lpr) lupus mouse models. Under this hypothesis, RUBICON deficiency should phenocopy NADPH oxidase deficiency, as both work in the same pathway. However, we observed the opposite — RUBICON deficiency resulted in reduced mortality, renal disease, and autoantibody titers to RNA-associated autoantigens. Given that our data contradict the published role for LAP in autoimmunity, we assessed whether CYBB and RUBICON are requisite for LAP. We found that LAP is not dependent on either of these 2 pathways. To our knowledge, our data reveal RUBICON as a novel regulator of SLE, possibly by a B cell–intrinsic mechanism, but do not support a role for LAP in lupus. American Society for Clinical Investigation 2022-04-08 /pmc/articles/PMC9057630/ /pubmed/35192551 http://dx.doi.org/10.1172/jci.insight.155537 Text en © 2022 Gordon et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Gordon, Rachael A.
Giannouli, Christina
Raparia, Chirag
Bastacky, Sheldon I.
Marinov, Anthony
Hawse, William
Cattley, Richard
Tilstra, Jeremy S.
Campbell, Allison M.
Nickerson, Kevin M.
Davidson, Anne
Shlomchik, Mark J.
Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis
title Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis
title_full Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis
title_fullStr Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis
title_full_unstemmed Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis
title_short Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis
title_sort rubicon promotes rather than restricts murine lupus and is not required for lc3-associated phagocytosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057630/
https://www.ncbi.nlm.nih.gov/pubmed/35192551
http://dx.doi.org/10.1172/jci.insight.155537
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