Snx10: a newly identified locus associated with human osteopetrosis

Ye, Liang; Morse, Leslie R.; Battaglino, Ricardo A.

doi:10.1038/bonekey.2013.155

Cited by 6 publications

(8 citation statements)

References 25 publications

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“…Inability to form osteoclasts or loss/altered osteoclast function leads to osteopetrosis, a heterogeneous group of rare disorders characterized by increased bone mass . We have shown previously that the gene encoding sorting nexin 10 (Snx10) is required for osteoclast formation and resorption activity and that Snx10 is a newly identified locus associated with human osteopetrosis . Furthermore, using mice harboring an Snx10‐inactivating insertion, we showed that global Snx10 deficiency caused osteopetrorickets as a result of not only failed osteoclast activity but also loss of gastric acid production and calcium absorption …”

Section: Introductionmentioning

confidence: 99%

FKBP12: A partner of Snx10 required for vesicular trafficking in osteoclasts

Battaglino

Jha

Sultana

et al. 2019

J of Cellular Biochemistry

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Osteoclasts employ highly specialized intracellular trafficking controls for bone resorption and organelle homeostasis. The sorting nexin Snx10 is a (Phosphatidylinositol 3-phosphate) PI3P-binding protein, which localizes to osteoclast early endosomes. Osteoclasts from humans and mice lacking functional Snx10 are severely dysfunctional. They show marked impairments in endocytosis, extracellular acidification, ruffled border formation, and bone resorption, suggesting that Snx10 regulates membrane trafficking. To better understand how SNx10 regulates vesicular formation and trafficking in osteoclasts, we set out on a search for Snx10 partners. We performed a yeast two-hybrid screening and identified FKBP12. FKBP12 is expressed in receptor activator of nuclear factor kB ligand-stimulated RAW264.7 monocytes, coimmunoprecipitates with Snx10, and colocalizes with Snx10 in osteoclasts. We also found that FKBP12, Snx10, and early endosome antigen 1 (EEA1) are present in the same subcellular fractions obtained by centrifugation in sucrose gradients, which confirms localization of FKBP12 to early endosomes. Taken together, these results indicate that Snx10 and FKBP12 are partners and suggest that Snx10 and FKBP12 are involved in the regulation of endosome/lysosome homeostasis via the synthesis. These findings may suggest novel therapeutic approaches to control bone loss by targeting essential steps in osteoclast membrane trafficking. K E Y W O R D S osteoclast, resorption, vesicular trafficking J Cell Biochem. 2019;120:13321-13329.wileyonlinelibrary.com/journal/jcb

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Section: Introductionmentioning

confidence: 99%

FKBP12: A partner of Snx10 required for vesicular trafficking in osteoclasts

Battaglino

Jha

Sultana

et al. 2019

J of Cellular Biochemistry

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“…4 We and others have shown previously that the gene encoding sorting nexin 10 (Snx10) is required for osteoclast morphogenesis and resorptive activity, 5 and, further, that SNX10 is in a locus associated with human osteopetrosis. 6,7 Snx10 is a member of the sorting nexin family of proteins and plays crucial roles in cargo sorting in the endosomal pathway. 8 Its overexpression causes dramatic enlargement of endosomes and blocks the endosome-to-lysosome transition.…”

Section: Introductionmentioning

confidence: 99%

Snx10 and PIKfyve are required for lysosome formation in osteoclasts

Sultana

Morse

Picotto

et al. 2019

J of Cellular Biochemistry

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Bone resorption and organelle homeostasis in osteoclasts require specialized intracellular trafficking. Sorting nexin 10 (Snx10) is a member of the sorting nexin family of proteins that plays crucial roles in cargo sorting in the endosomal pathway by its binding to phosphoinositide(3)phosphate (PI3P) localized in early endosomes. We and others have shown previously that the gene encoding sorting Snx10 is required for osteoclast morphogenesis and function, as osteoclasts from humans and mice lacking functional Snx10 are dysfunctional. To better understand the role and mechanisms by which Snx10 regulates vesicular transport, the aim of the present work was to study PIKfyve, another PI3P‐binding protein, which phosphorylates PI3P to PI(3,5)P2. PI(3,5)P2 is known to be required for endosome/lysosome maturation, and the inhibition of PIKfyve causes endosome enlargement. Overexpression of Snx10 also induces accumulation of early endosomes suggesting that both Snx10 and PIKfyve are required for normal endosome/lysosome transition. Apilimod is a small molecule with specific, nanomolar inhibitory activity on PIKfyve but only in the presence of key osteoclast factors CLCN7, OSTM1, and Snx10. This observation suggests that apilimod's inhibitory effects are mediated by endosome/lysosome disruption. Here we show that both Snx10 and PIKfyve colocalize to early endosomes in osteoclasts and coimmunoprecipitate in vesicle fractions. Treatment with 10 nM apilimod or genetic deletion of PIKfyve in cells resulted in the accumulation of early endosomes, and in the inhibition of osteoclast differentiation, lysosome formation, and secretion of TRAP from differentiated osteoclasts. Snx10 and PIKfyve also colocalized in gastric zymogenic cells, another cell type impacted by Snx10 mutations. Apilimod‐specific inhibition of PIKfyve required Snx10 expression, as it did not inhibit lysosome biogenesis in Snx10‐deficient osteoclasts. These findings suggest that Snx10 and PIKfyve are involved in the regulation of endosome/lysosome homeostasis via the synthesis of PI(3,5)P2 and may point to a new strategy to prevent bone loss.

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“…Recently, gene studies of osteopetrosis showed that human Sorting Nexin 10 (SNX10) could be a new target involved in this disease formation . SNX10 belongs to the large family of sorting nexin (SNX).…”

Section: Introductionmentioning

confidence: 99%

“…Based on sequence alignment, we speculated that the new PXe domain also existed in SNX10 and was responsible for SNX10 vacuolation activity. Homology models of SNX10 have been constructed in recent studies, and they were based on the conventional PX domain only . To better understand the roles of SNX10 in vesicular sorting, trafficking and the exact impacts of those disease‐related mutations, we solved the crystal structures of human SNX10 with a C42A mutation and the wild type SNX10.…”

Section: Introductionmentioning

confidence: 99%

Structure of human SNX10 reveals insights into its role in human autosomal recessive osteopetrosis

et al. 2014

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Sorting nexin 10 (SNX10), the unique member of the SNX family having vacuolation activity in cells, was shown to be involved in the development of autosomal recessive osteopetrosis (ARO) in recent genetic studies. However, the molecular mechanism of the disease-related mutations affecting the biological function of SNX10 is unclear. Here, we report the crystal structure of human SNX10 to 2.6 Å resolution. The structure reveals that SNX10 contains the extended phox-homology domain we previously proposed. Our study provides the structural details of those disease-related mutations. Combined with the vacuolation study of those mutations, we found that Tyr32 and Arg51 are important for the protein stability and both play a critical role in vacuolation activity, while Arg16Leu may affect the function of SNX10 in osteoclast through protein-protein interactions.

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Snx10: a newly identified locus associated with human osteopetrosis

Cited by 6 publications

References 25 publications

FKBP12: A partner of Snx10 required for vesicular trafficking in osteoclasts

FKBP12: A partner of Snx10 required for vesicular trafficking in osteoclasts

Snx10 and PIKfyve are required for lysosome formation in osteoclasts

Structure of human SNX10 reveals insights into its role in human autosomal recessive osteopetrosis

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