摘要：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.
