Overlapping functions of lysosomal acid phosphatase (LAP) and tartrate-resistant acid phosphatase (Acp5) revealed by doubly deficient mice

Abstract

To date, two lysosomal acid phosphatases are known to be expressed in cells of the monocyte/phagocyte lineage: the ubiquitously expressed lysosomal acid phosphatase (LAP) and the tartrate-resistant acid phosphatase-type 5 (Acp5). Deficiency of either acid phosphatase results in relatively mild phenotypes, suggesting that these enzymes may be capable of mutual complementation. This prompted us to generate LAP/Acp5 doubly deficient mice. LAP/Acp5 doubly deficient mice are viable and fertile but display marked alterations in soft and mineralised tissues. They are characterised by a progressive hepatosplenomegaly, gait disturbances and exaggerated foreshortening of long bones. Histologically, these animals are distinguished by an excessive lysosomal storage in macrophages of the liver, spleen, bone marrow, kidney and by altered growth plates. Microscopic analyses showed an accumulation of osteopontin adjacent to actively resorbing osteoclasts of Acp5- and LAP/Acp5-deficient mice. In osteoclasts of phosphatase-deficient mice, vacuoles were frequently found which contained fine filamentous material. The vacuoles in Acp5- and LAP/Acp5 doubly-deficient osteoclasts also contained crystallite-like features, as well as osteopontin, suggesting that Acp5 is important for processing of this protein. This is further supported by biochemical analyses that demonstrate strongly reduced dephosphorylation of osteopontin incubated with LAP/Acp5-deficient bone extracts. Fibroblasts derived from LAP/Acp5 deficient embryos were still able to dephosphorylate mannose 6-phosphate residues of endocytosed arylsulfatase A. We conclude that for several substrates LAP and Acp5 can substitute for each other and that these acid phosphatases are essential for processing of non-collagenous proteins, including osteopontin, by osteoclasts.

Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs

“…Therefore, we tested whether accumulation of HER2-HApt-AuNS complexes in lysosomes affected lysosomal activity by comparing the levels of lysosomal marker enzymes. 54 We measured acid phosphatase, an acid hydrolase commonly in lysosomes, 55 from cell-cultured media and cell lysates after 24 h incubation of free HApt and HApt-AuNS. The assay demonstrated that HApt-AuNS induced a 1.5 ((0.2) times increase of acid phosphatase levels in cells compared to free HApt.…”

Enamel defects in Acp4R110C/R110C mice and human ACP4 mutations

“…However, all ACP4 orthologs do not have the critical tyrosine of “YXXØ” motif or other known lysosome sorting signals, suggesting that ACP4 is primarily not a lysosomal protein. Moreover, in the Acp4 R110 C/R110C mouse incisor, secretory stage ameloblasts do not show significantly enlarged lysosomes, which are commonly seen in specific cells of mice lacking one of the lysosomal acid phosphatases, including ACP2, ACP3, and ACP5 66 , 67 . Collectively, all these pieces of evidence indicate that ACP4 probably does not function as a lysosomal degradative enzyme during enamel formation.…”

Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4

“…It will be interesting to investigate whether ACP2 and ACP5 also function as nucleotide phosphatases. It is perhaps significant that deficiency of these phosphatases is linked to inflammatory diseases [58,59], which we would predict arise from the resulting inhibition of PLD3 or PLD4 with attendant activation of nucleic acid sensors. In any case, some RNA virus genomes carry 5′-monophosphate [60], which may inhibit PLD3 and PLD4, possibly triggering downstream sensors for host innate immunity.…”