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The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling.

Tsang HT, Edwards TL, Wang X, Connell JW, Davies RJ, Durrington HJ, O'Kane CJ, Luzio JP, Reid E - Hum. Mol. Genet. (2009)

Bottom Line: NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII.Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1.In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signalling.

View Article: PubMed Central - PubMed

Affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, UK.

ABSTRACT
The hereditary spastic paraplegias (HSPs) are genetic conditions characterized by distal axonopathy of the longest corticospinal tract axons, and so their study provides an important opportunity to understand mechanisms involved in axonal maintenance and degeneration. A group of HSP genes encode proteins that localize to endosomes. One of these is NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) and we have shown recently that its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP) signalling, although the relevance of this finding to the mammalian protein was not known. We show here that mammalian NIPA1 is also an inhibitor of BMP signalling. NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII. We show that the mechanism by which NIPA1 inhibits BMP signalling involves downregulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1. In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signalling. Since BMP signalling is important for distal axonal function, we propose that dysregulation of BMP signalling could be a unifying pathological component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.

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NIPA1 promotes traffic of BMPRII to a lysosomal compartment in neuronal cells. (A and B) Wild-type NSC34 cells (A) or NSC34 cells stably expressing NIPA1-GFP (B) were transiently transfected with myc-BMPRII and labelled with the lysosomal marker Lamp1. Note the appearance of strong co-localization between BMPRII and Lamp1 in the NIPA1-GFP-expressing cell. Arrows indicate selected individual vesicles that show co-localization. (C) Count of vesicles doubly positive for myc-BMPRII and Lamp1 in wild-type NSC34 cells (32 cells) or stably expressing NIPA1-GFP (35 cells). Note the increase in the number of puncta showing co-localization between Lamp1 and myc-BMPRII in the NIPA1-stable cells. Error bars: SEM. P-value was calculated using unpaired t-test.
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DDP324F4: NIPA1 promotes traffic of BMPRII to a lysosomal compartment in neuronal cells. (A and B) Wild-type NSC34 cells (A) or NSC34 cells stably expressing NIPA1-GFP (B) were transiently transfected with myc-BMPRII and labelled with the lysosomal marker Lamp1. Note the appearance of strong co-localization between BMPRII and Lamp1 in the NIPA1-GFP-expressing cell. Arrows indicate selected individual vesicles that show co-localization. (C) Count of vesicles doubly positive for myc-BMPRII and Lamp1 in wild-type NSC34 cells (32 cells) or stably expressing NIPA1-GFP (35 cells). Note the increase in the number of puncta showing co-localization between Lamp1 and myc-BMPRII in the NIPA1-stable cells. Error bars: SEM. P-value was calculated using unpaired t-test.

Mentions: In HeLa cells depleted of NIPA1, BMPRII remained predominantly at the plasma membrane (data not shown). In NSC34 cells stably expressing NIPA1-GFP, the reduction of myc-BMPRII at the plasma membrane was not as dramatic as seen in HeLa NIPA1-GFP stable cells. Nevertheless, expression of NIPA1 resulted in the appearance of much stronger co-localization between BMPRII and lysosomes than was seen in wild-type NSC34 cells (Fig. 4A–C). Thus, expression of NIPA1 caused redistribution of BMPRII from the plasma membrane to endosomal and lysosomal compartments, in neuronal and non-neuronal cells, and this redistribution did not depend on BMPRII tail sequences.


The hereditary spastic paraplegia proteins NIPA1, spastin and spartin are inhibitors of mammalian BMP signalling.

Tsang HT, Edwards TL, Wang X, Connell JW, Davies RJ, Durrington HJ, O'Kane CJ, Luzio JP, Reid E - Hum. Mol. Genet. (2009)

NIPA1 promotes traffic of BMPRII to a lysosomal compartment in neuronal cells. (A and B) Wild-type NSC34 cells (A) or NSC34 cells stably expressing NIPA1-GFP (B) were transiently transfected with myc-BMPRII and labelled with the lysosomal marker Lamp1. Note the appearance of strong co-localization between BMPRII and Lamp1 in the NIPA1-GFP-expressing cell. Arrows indicate selected individual vesicles that show co-localization. (C) Count of vesicles doubly positive for myc-BMPRII and Lamp1 in wild-type NSC34 cells (32 cells) or stably expressing NIPA1-GFP (35 cells). Note the increase in the number of puncta showing co-localization between Lamp1 and myc-BMPRII in the NIPA1-stable cells. Error bars: SEM. P-value was calculated using unpaired t-test.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2748891&req=5

DDP324F4: NIPA1 promotes traffic of BMPRII to a lysosomal compartment in neuronal cells. (A and B) Wild-type NSC34 cells (A) or NSC34 cells stably expressing NIPA1-GFP (B) were transiently transfected with myc-BMPRII and labelled with the lysosomal marker Lamp1. Note the appearance of strong co-localization between BMPRII and Lamp1 in the NIPA1-GFP-expressing cell. Arrows indicate selected individual vesicles that show co-localization. (C) Count of vesicles doubly positive for myc-BMPRII and Lamp1 in wild-type NSC34 cells (32 cells) or stably expressing NIPA1-GFP (35 cells). Note the increase in the number of puncta showing co-localization between Lamp1 and myc-BMPRII in the NIPA1-stable cells. Error bars: SEM. P-value was calculated using unpaired t-test.
Mentions: In HeLa cells depleted of NIPA1, BMPRII remained predominantly at the plasma membrane (data not shown). In NSC34 cells stably expressing NIPA1-GFP, the reduction of myc-BMPRII at the plasma membrane was not as dramatic as seen in HeLa NIPA1-GFP stable cells. Nevertheless, expression of NIPA1 resulted in the appearance of much stronger co-localization between BMPRII and lysosomes than was seen in wild-type NSC34 cells (Fig. 4A–C). Thus, expression of NIPA1 caused redistribution of BMPRII from the plasma membrane to endosomal and lysosomal compartments, in neuronal and non-neuronal cells, and this redistribution did not depend on BMPRII tail sequences.

Bottom Line: NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII.Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1.In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signalling.

View Article: PubMed Central - PubMed

Affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, UK.

ABSTRACT
The hereditary spastic paraplegias (HSPs) are genetic conditions characterized by distal axonopathy of the longest corticospinal tract axons, and so their study provides an important opportunity to understand mechanisms involved in axonal maintenance and degeneration. A group of HSP genes encode proteins that localize to endosomes. One of these is NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) and we have shown recently that its Drosophila homologue spichthyin inhibits bone morphogenic protein (BMP) signalling, although the relevance of this finding to the mammalian protein was not known. We show here that mammalian NIPA1 is also an inhibitor of BMP signalling. NIPA1 physically interacts with the type II BMP receptor (BMPRII) and we demonstrate that this interaction does not require the cytoplasmic tail of BMPRII. We show that the mechanism by which NIPA1 inhibits BMP signalling involves downregulation of BMP receptors by promoting their endocytosis and lysosomal degradation. Disease-associated mutant versions of NIPA1 alter the trafficking of BMPRII and are less efficient at promoting BMPRII degradation than wild-type NIPA1. In addition, we demonstrate that two other members of the endosomal group of HSP proteins, spastin and spartin, are inhibitors of BMP signalling. Since BMP signalling is important for distal axonal function, we propose that dysregulation of BMP signalling could be a unifying pathological component in this endosomal group of HSPs, and perhaps of importance in other conditions in which distal axonal degeneration is found.

Show MeSH
Related in: MedlinePlus