Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.23.5 (
cathepsin D
)
4,130
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We previously observed that
SNAPIN
, which is an adaptor protein in the SNARE core complex, was highly expressed in rheumatoid arthritis synovial tissue macrophages, but its role in macrophages and autoimmunity is unknown. To identify
SNAPIN
's role in these cells, we employed siRNA to silence the expression of
SNAPIN
in primary human macrophages. Silencing
SNAPIN
resulted in swollen lysosomes with impaired CTSD (
cathepsin D
) activation, although total CTSD was not reduced. Neither endosome cargo delivery nor lysosomal fusion with endosomes or autophagosomes was inhibited following the forced silencing of
SNAPIN
. The acidification of lysosomes and accumulation of autolysosomes in
SNAPIN
-silenced cells was inhibited, resulting in incomplete lysosomal hydrolysis and impaired macroautophagy/autophagy flux. Mechanistic studies employing ratiometric color fluorescence on living cells demonstrated that the reduction of
SNAPIN
resulted in a modest reduction of H
+
pump activity; however, the more critical mechanism was a lysosomal proton leak. Overall, our results demonstrate that
SNAPIN
is critical in the maintenance of healthy lysosomes and autophagy through its role in lysosome acidification and autophagosome maturation in macrophages largely through preventing proton leak. These observations suggest an important role for
SNAPIN
and autophagy in the homeostasis of macrophages, particularly long-lived tissue resident macrophages.
...
PMID:SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages. 2792 5
