Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function

Abstract We have previously shown that the DBA/2J versus AKR/J mouse strain is associated with decreased autophagy-mediated lysosomal hydrolysis of cholesterol esters. Our objective was to determine differences in lysosome function in AKR/J and DBA/2J macrophages, and identify the responsible genes....

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Autores principales:	Peggy Robinet, Brian Ritchey, Shuhui Wang Lorkowski, Alexander M. Alzayed, Sophia DeGeorgia, Eve Schodowski, C. Alicia Traughber, Jonathan D. Smith
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2eadfff2977f44acae1459d96f9ec631
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spelling	oai:doaj.org-article:2eadfff2977f44acae1459d96f9ec6312021-12-02T15:43:24ZQuantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function10.1038/s41598-021-89800-52045-2322https://doaj.org/article/2eadfff2977f44acae1459d96f9ec6312021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89800-5https://doaj.org/toc/2045-2322Abstract We have previously shown that the DBA/2J versus AKR/J mouse strain is associated with decreased autophagy-mediated lysosomal hydrolysis of cholesterol esters. Our objective was to determine differences in lysosome function in AKR/J and DBA/2J macrophages, and identify the responsible genes. Using a novel dual-labeled indicator of lysosome function, DBA/2J versus AKR/J bone marrow derived macrophages had significantly decreased lysosome function. We performed quantitative trait loci mapping of lysosome function in bone marrow macrophages from an AKR/J × DBA/2J strain intercross. Four distinct lysosome function loci were identified, which we named macrophage lysosome function modifier (Mlfm) Mlfm1 through Mlfm4. The strongest locus Mlfm1 harbors the Gpnmb gene, which has been shown to recruit autophagy protein light chain 3 to autophagosomes for lysosome fusion. The parental DBA/2J strain has a nonsense variant in Gpnmb. siRNA knockdown of Gpnmb in AKR/J macrophages decreased lysosome function, and Gpnmb deletion through CRISP/Cas9 editing in RAW 264.7 mouse macrophages also demonstrated a similar result. Furthermore, a DBA/2 substrain, called DBA/2J-Gpnmb+/SjJ, contains the wildtype Gpnmb gene, and macrophages from this Gpnmb-preserved DBA/2 substrain exhibited recovered lysosome function. In conclusion, we identified Gpnmb as a causal modifier gene of lysosome function in this strain pair.Peggy RobinetBrian RitcheyShuhui Wang LorkowskiAlexander M. AlzayedSophia DeGeorgiaEve SchodowskiC. Alicia TraughberJonathan D. SmithNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Peggy Robinet Brian Ritchey Shuhui Wang Lorkowski Alexander M. Alzayed Sophia DeGeorgia Eve Schodowski C. Alicia Traughber Jonathan D. Smith Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function
description	Abstract We have previously shown that the DBA/2J versus AKR/J mouse strain is associated with decreased autophagy-mediated lysosomal hydrolysis of cholesterol esters. Our objective was to determine differences in lysosome function in AKR/J and DBA/2J macrophages, and identify the responsible genes. Using a novel dual-labeled indicator of lysosome function, DBA/2J versus AKR/J bone marrow derived macrophages had significantly decreased lysosome function. We performed quantitative trait loci mapping of lysosome function in bone marrow macrophages from an AKR/J × DBA/2J strain intercross. Four distinct lysosome function loci were identified, which we named macrophage lysosome function modifier (Mlfm) Mlfm1 through Mlfm4. The strongest locus Mlfm1 harbors the Gpnmb gene, which has been shown to recruit autophagy protein light chain 3 to autophagosomes for lysosome fusion. The parental DBA/2J strain has a nonsense variant in Gpnmb. siRNA knockdown of Gpnmb in AKR/J macrophages decreased lysosome function, and Gpnmb deletion through CRISP/Cas9 editing in RAW 264.7 mouse macrophages also demonstrated a similar result. Furthermore, a DBA/2 substrain, called DBA/2J-Gpnmb+/SjJ, contains the wildtype Gpnmb gene, and macrophages from this Gpnmb-preserved DBA/2 substrain exhibited recovered lysosome function. In conclusion, we identified Gpnmb as a causal modifier gene of lysosome function in this strain pair.
format	article
author	Peggy Robinet Brian Ritchey Shuhui Wang Lorkowski Alexander M. Alzayed Sophia DeGeorgia Eve Schodowski C. Alicia Traughber Jonathan D. Smith
author_facet	Peggy Robinet Brian Ritchey Shuhui Wang Lorkowski Alexander M. Alzayed Sophia DeGeorgia Eve Schodowski C. Alicia Traughber Jonathan D. Smith
author_sort	Peggy Robinet
title	Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function
title_short	Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function
title_full	Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function
title_fullStr	Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function
title_full_unstemmed	Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function
title_sort	quantitative trait locus mapping identifies the gpnmb gene as a modifier of mouse macrophage lysosome function
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2eadfff2977f44acae1459d96f9ec631
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Quantitative trait locus mapping identifies the Gpnmb gene as a modifier of mouse macrophage lysosome function

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