The pink gene encodes the Drosophila orthologue of the human Hermansky–Pudlak syndrome 5 (HPS5) gene

Genome ◽  
2007 ◽  
Vol 50 (6) ◽  
pp. 548-556 ◽  
Author(s):  
Monika Syrzycka ◽  
Lori A. McEachern ◽  
Jennifer Kinneard ◽  
Kristel Prabhu ◽  
Kathleen Fitzpatrick ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Protein Complexes ◽  
Model Organism ◽  
Autosomal Recessive Disorders ◽  
Dense Granules ◽  
Eye Colour ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles ◽  
Key Participants

Hermansky–Pudlak syndrome (HPS) consists of a set of human autosomal recessive disorders, with symptoms resulting from defects in genes required for protein trafficking in lysosome-related organelles such as melanosomes and platelet dense granules. A number of human HPS genes and rodent orthologues have been identified whose protein products are key components of 1 of 4 different protein complexes (AP-3 or BLOC-1, -2, and -3) that are key participants in the process. Drosophila melanogaster has been a key model organism in demonstrating the in vivo significance of many genes involved in protein trafficking pathways; for example, mutations in the “granule group” genes lead to changes in eye colour arising from improper protein trafficking to pigment granules in the developing eye. An examination of the chromosomal positioning of Drosophila HPS gene orthologues suggested that CG9770, the Drosophila HPS5 orthologue, might correspond to the pink locus. Here we confirm this gene assignment, making pink the first eye colour gene in flies to be identified as a BLOC complex gene.

Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOC-1 complex

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3181-3189 ◽  
Author(s):  
Babette Gwynn ◽  
Jose A. Martina ◽  
Juan S. Bonifacino ◽  
Elena V. Sviderskaya ◽  
M. Lynn Lamoreux ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Trafficking ◽  
Protein Complexes ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Amino Acid Identity ◽  
Organelle Biogenesis ◽  
Hermansky Pudlak Syndrome ◽  
Human Orthologue ◽  
Lysosome Related Organelles

Abstract Hermansky-Pudlak syndrome (HPS), a disorder of organelle biogenesis, affects lysosomes, melanosomes, and platelet dense bodies. Seven genes cause HPS in humans (HPS1-HPS7) and at least 15 nonallelic mutations cause HPS in mice. Where their function is known, the HPS proteins participate in protein trafficking and vesicle docking/fusion events during organelle biogenesis. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; biogenesis of lysosome-related organelles complex 1 (BLOC-1), consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. Here, we report the cloning of the mouse HPS mutation reduced pigmentation (rp). We show that the wild-type rp gene encodes a novel, widely expressed 195-amino acid protein that shares 87% amino acid identity with its human orthologue and localizes to punctate cytoplasmic structures. Further, we show that phosphorylated RP is part of the BLOC-1 complex. In mutant rp/rp mice, a premature stop codon truncates the protein after 79 amino acids. Defects in all the 5 known components of BLOC-1, including RP, cause severe HPS in mice, suggesting that the subunits are nonredundant and that BLOC-1 plays a key role in organelle biogenesis.

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3–independent mechanism

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4227-4235 ◽  
Author(s):  
Babette Gwynn ◽  
Steven L. Ciciotte ◽  
Susan J. Hunter ◽  
Linda L. Washburn ◽  
Richard S. Smith ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
Protein Trafficking ◽  
Dense Body ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Chromosome 5 ◽  
Prolonged Bleeding ◽  
Independent Mechanism ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles

Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes ofcno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3–independent mechanism critical to the biogenesis of lysosome-related organelles.

scholarly journals BLOC-1 Interacts with BLOC-2 and the AP-3 Complex to Facilitate Protein Trafficking on Endosomes

2006 ◽  
Vol 17 (9) ◽  
pp. 4027-4038 ◽  
Author(s):  
Santiago M. Di Pietro ◽  
Juan M. Falcón-Pérez ◽  
Danièle Tenza ◽  
Subba R.G. Setty ◽  
Michael S. Marks ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Trafficking ◽  
Adaptor Protein ◽  
Early Endosome ◽  
Related Protein ◽  
Genes Encoding ◽  
Cellular Machinery ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles ◽  
Tyrosinase Related Protein

The adaptor protein (AP)-3 complex is a component of the cellular machinery that controls protein sorting from endosomes to lysosomes and specialized related organelles such as melanosomes. Mutations in an AP-3 subunit underlie a form of Hermansky-Pudlak syndrome (HPS), a disorder characterized by abnormalities in lysosome-related organelles. HPS in humans can also be caused by mutations in genes encoding subunits of three complexes of unclear function, named biogenesis of lysosome-related organelles complex (BLOC)-1, -2, and -3. Here, we report that BLOC-1 interacts physically and functionally with AP-3 to facilitate the trafficking of a known AP-3 cargo, CD63, and of tyrosinase-related protein 1 (Tyrp1), a melanosomal membrane protein previously thought to traffic only independently of AP-3. BLOC-1 also interacts with BLOC-2 to facilitate Tyrp1 trafficking by a mechanism apparently independent of AP-3 function. Both BLOC-1 and -2 localize mainly to early endosome-associated tubules as determined by immunoelectron microscopy. These findings support the idea that BLOC-1 and -2 represent hitherto unknown components of the endosomal protein trafficking machinery.

scholarly journals Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1)

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4402-4407 ◽  
Author(s):  
Steven L. Ciciotte ◽  
Babette Gwynn ◽  
Kengo Moriyama ◽  
Marjan Huizing ◽  
William A. Gahl ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Complexes ◽  
Mutation Screening ◽  
Organelle Biogenesis ◽  
Vesicle Docking ◽  
Dense Bodies ◽  
Associated Proteins ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles ◽  
Novel Protein

Abstract Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis affecting 3 related organelles—melanosomes, platelet dense bodies, and lysosomes. Four genes causing HPS in humans (HPS1-HPS4) are known, and at least 15 nonallelic mutations cause HPS in the mouse. Where their functions are known, the HPS-associated proteins are involved in some aspect of intracellular vesicular trafficking, that is, protein sorting and vesicle docking and fusion. Biochemical and genetic evidence indicates that the HPS-associated genes encode components of at least 3 distinct protein complexes: the adaptor complex AP-3; the HPS1/HPS4 complex; and BLOC-1 (biogenesis of lysosome-related organelles complex-1), consisting of the proteins encoded at 2 mouse HPS loci, pallid (pa) and muted (mu), and at least 3 other unidentified proteins. Here, we report the cloning of the mouse HPS mutation cappuccino (cno). We show that the wild-type cno gene encodes a novel, ubiquitously expressed cytoplasmic protein that coassembles with pallidin and the muted protein in the BLOC-1 complex. Further, we identify a frameshift mutation in mutant cno/cno mice. The C-terminal 81 amino acids are replaced with 72 different amino acids in the mutant CNO protein, and its ability to interact in BLOC-1 is abolished. We performed mutation screening of patients with HPS and failed to identify any CNO defects. Notably, although defects in components of the HPS1/HPS4 and the AP-3 complexes are associated with HPS in humans, no defects in the known components of BLOC-1 have been identified in 142 patients with HPS screened to date, suggesting that BLOC-1 function may be critical in humans.

scholarly journals A toolbox for efficient proximity-dependent biotinylation in zebrafish embryos

2021 ◽  
Author(s):  
Shimon M Rosenthal ◽  
Tvisha Misra ◽  
Hala Abdouni ◽  
Tess C Branon ◽  
Alice Y Ting ◽  
...  
Keyword(s):  
Cell Culture ◽  
Fluorescent Protein ◽  
Protein Complexes ◽  
Mammalian Cell Culture ◽  
Model Organism ◽  
Negative Control ◽  
Lamin A ◽  
Zebrafish Embryos ◽  
Time Resolved

Understanding how proteins are organized in compartments is essential to elucidating their function. While proximity-dependent approaches such as BioID have enabled a massive increase in information about organelles, protein complexes and other structures in cell culture, to date there have been only a few studies in living vertebrates. Here, we adapted proximity labeling for protein discovery in vivo in the vertebrate model organism, zebrafish. Using lamin A (LMNA) as bait and green fluorescent protein (GFP) as a negative control, we developed, optimized, and benchmarked in vivo TurboID and miniTurbo labeling in early zebrafish embryos. We developed both an mRNA injection protocol and a transgenic system in which transgene expression is controlled by a heat shock promoter. In both cases, biotin is provided directly in the egg water, and we demonstrate that 12 hours of labeling are sufficient for biotinylation of prey proteins, which should permit time-resolved analysis of development. After statistical scoring, we found that the proximal partners of LMNA detected in each system were enriched for nuclear envelope and nuclear membrane proteins, and included many orthologs of human proteins identified as proximity partners of lamin A in mammalian cell culture. The tools and protocols developed here will allow zebrafish researchers to complement genetic tools with powerful proteomics approaches.

scholarly journals SLC35D3 delivery from megakaryocyte early endosomes is required for platelet dense granule biogenesis and is differentially defective in Hermansky-Pudlak syndrome models

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 404-414 ◽  
Author(s):  
Ronghua Meng ◽  
Yuhuan Wang ◽  
Yu Yao ◽  
Zhe Zhang ◽  
Dawn C. Harper ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Subcellular Fractionation ◽  
Dense Granule ◽  
Direct Role ◽  
Excessive Bleeding ◽  
Dense Granules ◽  
Early Endosomes ◽  
Hermansky Pudlak Syndrome ◽  
Endosomal Transport ◽  
Lysosome Related Organelles

Abstract Platelet dense granules are members of a family of tissue-specific, lysosome-related organelles that also includes melanosomes in melanocytes. Contents released from dense granules after platelet activation promote coagulation and hemostasis, and dense granule defects such as those seen in Hermansky-Pudlak syndrome (HPS) cause excessive bleeding, but little is known about how dense granules form in megakaryocytes (MKs). In the present study, we used SLC35D3, mutation of which causes a dense granule defect in mice, to show that early endosomes play a direct role in dense granule biogenesis. We show that SLC35D3 expression is up-regulated during mouse MK differentiation and is enriched in platelets. Using immunofluorescence and immunoelectron microscopy and subcellular fractionation in megakaryocytoid cells, we show that epitope-tagged and endogenous SLC35D3 localize predominantly to early endosomes but not to dense granule precursors. Nevertheless, SLC35D3 is depleted in mouse platelets from 2 of 3 HPS models and, when expressed ectopically in melanocytes, SLC35D3 localizes to melanosomes in a manner requiring a HPS-associated protein complex that functions from early endosomal transport intermediates. We conclude that SLC35D3 is either delivered to nascent dense granules from contiguous early endosomes as MKs mature or functions in dense granule biogenesis directly from early endosomes, suggesting that dense granules originate from early endosomes in MKs.

Defects in the cappuccino (cno) gene on mouse chromosome 5 and human 4p cause Hermansky-Pudlak syndrome by an AP-3–independent mechanism

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4227-4235 ◽  
Author(s):  
Babette Gwynn ◽  
Steven L. Ciciotte ◽  
Susan J. Hunter ◽  
Linda L. Washburn ◽  
Richard S. Smith ◽  
...  
Keyword(s):  
Mouse Chromosome ◽  
Protein Trafficking ◽  
Dense Body ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Chromosome 5 ◽  
Prolonged Bleeding ◽  
Independent Mechanism ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles

Abstract Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes ofcno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3–independent mechanism critical to the biogenesis of lysosome-related organelles.

scholarly journals A zinc transporter, transmembrane protein 163 (TMEM163), is critical for the biogenesis of platelet dense granules

Blood ◽  
2021 ◽  
Author(s):  
Yefeng Yuan ◽  
Teng Liu ◽  
Xiahe Huang ◽  
Yuanying Chen ◽  
Weilin Zhang ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Underlying Mechanism ◽  
Zinc Homeostasis ◽  
Intracellular Zinc ◽  
Dense Granules ◽  
Platelet Storage ◽  
New Findings ◽  
Hermansky Pudlak Syndrome ◽  
Lysosome Related Organelles ◽  
Deficient Mice

Lysosome-related organelles (LROs) are a category of secretory organelles enriched with ions such as Ca2+, which are maintained by ion transporters or channels. Homeostasis of these ions is important for LRO biogenesis and secretion. Hermansky-Pudlak syndrome (HPS) is a recessive disorder with defects in multiple LROs, typically platelet dense granules (DGs) and melanosomes. However, the underlying mechanism of DG deficiency is largely unknown. Using quantitative proteomics, we identified a previously unreported platelet Zn2+ transporter TMEM163, which was significantly reduced in BLOC-1 (Dtnbp1 sdy and Pldn pa), BLOC-2 (Hps6 ru) or AP-3 (Ap3b1 pe) deficient mice and HPS patients (HPS2, 3, 5, 6, or 9). We observed similar platelet DG defects and abnormal intracellular zinc accumulation in platelets of mice deficient in either TMEM163 or dysbindin (a BLOC-1 subunit). In addition, we discovered that BLOC-1 was required for the trafficking of TMEM163 to perinuclear DG and late endosome (LE) marker-positive compartments (likely DG precursors) in MEG-01 cells. Our results suggest that TMEM163 is critical for DG biogenesis and BLOC-1 is required for the trafficking of TMEM163 to putative DG precursors. These new findings suggest that loss of TMEM163 function results in disruption of intracellular zinc homeostasis, and provide insights into the pathogenesis of HPS or platelet storage pool deficiency.

scholarly journals Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis

2019 ◽  
Vol 3 (15) ◽  
pp. 2368-2380 ◽  
Author(s):  
Alicia Aguilar ◽  
Josiane Weber ◽  
Julie Boscher ◽  
Monique Freund ◽  
Catherine Ziessel ◽  
...  
Keyword(s):  
Coat Color ◽  
Spontaneous Mutation ◽  
Oculocutaneous Albinism ◽  
Dense Granule ◽  
Morphological Defects ◽  
Hermansky Pudlak Syndrome ◽  
Guanosine Triphosphatase ◽  
Lysosome Related Organelles ◽  
And Function

Abstract The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase Rab38. This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the cht mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for Rab32, Rab38, and both genes. Single Rab38 inactivation mimicked cht mice, whereas single Rab32 inactivation had no effect in DGs, coat color, or lung morphology. By contrast, Rab32/38 double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content.

Photoinhibition in vivo and in vitro Involves Weakly Coupled Chlorophyll–Protein Complexes‡¶

2002 ◽  
Vol 75 (6) ◽  
pp. 613 ◽  
Author(s):  
Stefano Santabarbara ◽  
Ilaria Cazzalini ◽  
Andrea Rivadossi ◽  
Flavio M. Garlaschi ◽  
Giuseppe Zucchelli ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Weakly Coupled ◽  
Chlorophyll Protein Complexes ◽  
Chlorophyll Protein
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