Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes

Tornieri, Karine; Zlatic, Stephanie A.; Mullin, Ariana P.; Werner, Erica; Harrison, Robert W.; L’Hernault, Steven W.; Faúndez, Víctor

doi:10.1093/hmg/ddt378

Cited by 25 publications

(24 citation statements)

References 63 publications

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“…It is tempting to speculate that two different forms of HOPS/CORVET, one containing VPS33A and another containing VPS33B, would mediate transport to DGs and α-granules, respectively. However, VPS33B may not form a complex with HOPS or CORVET and instead form a separate complex with VPS16B (also known VIPAS39 or VIPAR) [103, 108, 109]. …”

Section: Protein Machinerymentioning

confidence: 99%

Storage pool diseases illuminate platelet dense granule biogenesis

Ambrosio

Pietro

2016

Platelets

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Platelet dense granules are membrane bound compartments that store polyphosphate and small molecules such as ADP, ATP, Ca2+ and serotonin. The release of dense granule contents plays a central role in platelet aggregation to form a hemostatic plug. Accordingly, congenital deficiencies in the biogenesis of platelet dense granules underlie human genetic disorders that cause storage pool disease and manifest with prolonged bleeding. Dense granules belong to a family of lysosome-related organelles, which also includes melanosomes, the compartments where the melanin pigments are synthesized. These organelles share several characteristics including an acidic lumen and, at least in part, the molecular machinery involved in their biogenesis. As a result, many genes affect both dense granule and melanosome biogenesis and the corresponding patients present not only with bleeding but also with oculocutaneous albinism. The identification and characterization of such genes has been instrumental in dissecting the pathways responsible for organelle biogenesis. Because the study of melanosome biogenesis has advanced more rapidly, this knowledge has been extrapolat ed to explain how dense granules are produced. However, some progress has recently been made in studying platelet dense granule biogenesis directly in megakaryocytes and megakaryocytoid cells. Dense granules originate from an endosomal intermediate compartment, the multivesicular body. Maturation and differentiation into a dense granule begins when newly synthesized dense granule specific proteins are delivered from early/recycling endosomal compartments. The machinery that orchestrates this vesicular trafficking is composed of a combination of both ubiquitous and cell type specific proteins. Here we review the current knowledge on dense granule biogenesis. In particular, we focus on the individual human and murine genes encoding the molecular machinery involved in this process and how their deficiencies result in disease.

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Section: Protein Machinerymentioning

confidence: 99%

Storage pool diseases illuminate platelet dense granule biogenesis

Ambrosio

Pietro

2016

Platelets

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“…By contrast, a fob null mutation blocks the maturation of phagosomes (Akbar et al, 2011). fob encodes the Drosophila ortholog of Vps16B (VIPAS39), the binding partner of Vps33B (Cullinane et al, 2010; Pulipparacharuvil et al, 2005; Tornieri et al, 2013). This defect in phagosome maturation compromises bacterial clearance and renders fob flies susceptible to non-virulent microbial infections (Akbar et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with these observations, the mycobacterial virulence factor PtpA targets Vps33B for dephosphorylation, which contributes to intracellular persistence of Mycobacterium (Bach et al, 2008). Mutations in human Vps33B and VIPAS39 are responsible for arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome (Cullinane et al, 2010; Gissen et al, 2004), a fatal recessive disorder characterized by trafficking defects in multiple organ systems (Gissen et al, 2006; Tornieri et al, 2013) and persistent infections and sepsis (Jang et al, 2009; Seo et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination

et al. 2016

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Summary Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B.

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“…The core subunits Vps18 and Vps11 have one clear homolog in mammalian cells and Vps16 and Vps33 are both expressed as an A and B isoform. [17][18][19][20][25][26][27][28][29][30][31] The CORVET subunit Vps8 and the HOPS Vps41 have one corresponding homolog in higher eukaryotes. 24,27 Vps39 has 2 homologs: Vps39-1/ hVam6/TLP and Vps39-2/TRAP1.…”

Section: Introductionmentioning

confidence: 99%

The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET

et al. 2014

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Membrane fusion in the endocytic pathway is mediated by a protein machinery consistent of Rab GTPases, tethering factors and SNAREs. In yeast, the endosomal CORVET and lysosomal HOPS tethering complexes share 4 of their 6 subunits. The 2 additional subunits in each complex -Vps3 and Vps8 for CORVET, and the homologous Vps39 and Vps41 for HOPS -bind directly to Rab5 and Rab7, respectively. In humans, all subunits for HOPS have been described. However, human CORVET remains poorly characterized and a homolog of Vps3 is still missing. Here we characterize 2 previously identified Vps39 isoforms, hVps39-1/hVam6/TLP and hVps39-2/TRAP1, in yeast and HEK293 cells. None of them can compensate the loss of the endogenous yeast Vps39, though the specific interaction of hVps39-1 with the virus-specific LT protein was reproduced. Both human Vps39 proteins show a cytosolic localization in yeast and mammalian cells. However, hVps39-2/TRAP1 strongly co-localizes with co-expressed Rab5 and interacts directly with Rab5-GTP in vitro. We conclude that hVps39-2/TRAP1 is an endosomal protein and an effector of Rab5, suggesting a role of the protein as a subunit of the putative human CORVET complex.

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Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes

Cited by 25 publications

References 63 publications

Storage pool diseases illuminate platelet dense granule biogenesis

Storage pool diseases illuminate platelet dense granule biogenesis

ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination

The Vps39-like TRAP1 is an effector of Rab5 and likely the missing Vps3 subunit of human CORVET

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