scholarly journals The full-of-bacteria gene is required for phagosome maturation during immune defense in Drosophila

2011 ◽  
Vol 192 (3) ◽  
pp. 383-390 ◽  
Author(s):  
Mohammed Ali Akbar ◽  
Charles Tracy ◽  
Walter H.A. Kahr ◽  
Helmut Krämer
Keyword(s):  
Renal Dysfunction ◽  
Immune Defense ◽  
Specific Requirement ◽  
Phagosome Maturation ◽  
Late Endosomes ◽  
Arc Syndrome ◽  
Hops Complex

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a fatal recessive disorder caused by mutations in the VPS33B or VPS16B genes. Both encode homologues of the Vps33p and Vps16p subunits of the HOPS complex necessary for fusions of vacuoles in yeast. Here, we describe a mutation in the full-of-bacteria (fob) gene, which encodes Drosophila Vps16B. Flies null for fob are homozygous viable and fertile. They exhibit, however, a defect in their immune defense that renders them hypersensitive to infections with nonpathogenic bacteria. fob hemocytes (fly macrophages) engulf bacteria but fail to digest them. Phagosomes undergo early steps of maturation and transition to a Rab7-positive stage, but do not mature to fully acidified phagolysosomes. This reflects a specific requirement of fob in the fusion of phagosomes with late endosomes/lysosomes. In contrast, cargo of autophagosomes as well as endosomes exhibit normal lysosomal delivery in fob cells. These findings suggest that defects in phagosome maturation may contribute to symptoms of ARC patients including recurring infections.

scholarly journals TBC-2 Regulates RAB-5/RAB-7-mediated Endosomal Trafficking inCaenorhabditis elegans

2010 ◽  
Vol 21 (13) ◽  
pp. 2285-2296 ◽  
Author(s):  
Laëtitia Chotard ◽  
Ashwini K. Mishra ◽  
Marc-André Sylvain ◽  
Simon Tuck ◽  
David G. Lambright ◽  
...  
Keyword(s):  
Rab Gtpase ◽  
Endosomal Trafficking ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Late Endosomes ◽  
Arginine Finger ◽  
Endosome Maturation ◽  
Hops Complex

During endosome maturation the early endosomal Rab5 GTPase is replaced with the late endosomal Rab7 GTPase. It has been proposed that active Rab5 can recruit and activate Rab7, which in turn could inactivate and remove Rab5. However, many of the Rab5 and Rab7 regulators that mediate endosome maturation are not known. Here, we identify Caenorhabditis elegans TBC-2, a conserved putative Rab GTPase-activating protein (GAP), as a regulator of endosome to lysosome trafficking in several tissues. We show that tbc-2 mutant animals accumulate enormous RAB-7–positive late endosomes in the intestine containing refractile material. RAB-5, RAB-7, and components of the homotypic fusion and vacuole protein sorting (HOPS) complex, a RAB-7 effector/putative guanine nucleotide exchange factor (GEF), are required for the tbc-2(−) intestinal phenotype. Expression of activated RAB-5 Q78L in the intestine phenocopies the tbc-2(−) large late endosome phenotype in a RAB-7 and HOPS complex-dependent manner. TBC-2 requires the catalytic arginine-finger for function in vivo and displays the strongest GAP activity on RAB-5 in vitro. However, TBC-2 colocalizes primarily with RAB-7 on late endosomes and requires RAB-7 for membrane localization. Our data suggest that TBC-2 functions on late endosomes to inactivate RAB-5 during endosome maturation.

scholarly journals Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome

2004 ◽  
Vol 36 (4) ◽  
pp. 400-404 ◽  
Author(s):  
Paul Gissen ◽  
Colin A Johnson ◽  
Neil V Morgan ◽  
Janneke M Stapelbroek ◽  
Tim Forshew ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Renal Dysfunction ◽  
Arc Syndrome

scholarly journals The Role of Platelets and ε-Aminocaproic Acid in Arthrogryposis, Renal Dysfunction, and Cholestasis (ARC) Syndrome Associated Hemorrhage

2015 ◽  
Vol 63 (3) ◽  
pp. 561-563 ◽  
Author(s):  
Angela C. Weyand ◽  
Rebecca M. Lombel ◽  
Steven W. Pipe ◽  
Jordan A. Shavit
Keyword(s):  
Renal Dysfunction ◽  
Aminocaproic Acid ◽  
Arc Syndrome

Haematological manifestations of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: A case report

2013 ◽  
Vol 14 (1) ◽  
pp. 26-28 ◽  
Author(s):  
Omar I. Saadah ◽  
Bayan E. Bokhari ◽  
Taghreed M. Alshaeri ◽  
Wasil Jastaniah
Keyword(s):  
Case Report ◽  
Renal Dysfunction ◽  
Arc Syndrome

VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: Incomplete ARC syndrome phenotype

2006 ◽  
Vol 148 (2) ◽  
pp. 269-271 ◽  
Author(s):  
Laura N. Bull ◽  
Venus Mahmoodi ◽  
Alastair J. Baker ◽  
Rosamond Jones ◽  
Sandra S. Strautnieks ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Arc Syndrome

scholarly journals A vesicle surface tyrosine kinase regulates phagosome maturation

2007 ◽  
Vol 178 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Jun Fang ◽  
Joseph A. Brzostowski ◽  
Stephen Ou ◽  
Nilgun Isik ◽  
Vinod Nair ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Control Mechanism ◽  
Kinase Domain ◽  
Microbial Pathogens ◽  
Phagosome Maturation ◽  
Tyrosine Kinase Signaling ◽  
Late Endosomes

Phagocytosis is crucial for host defense against microbial pathogens and for obtaining nutrients in Dictyostelium discoideum. Phagocytosed particles are delivered via a complex route from phagosomes to lysosomes for degradation, but the molecular mechanisms involved in the phagosome maturation process are not well understood. Here, we identify a novel vesicle-associated receptor tyrosine kinase-like protein, VSK3, in D. discoideum. We demonstrate how VSK3 is involved in phagosome maturation. VSK3 resides on the membrane of late endosomes/lysosomes with its C-terminal kinase domain facing the cytoplasm. Inactivation of VSK3 by gene disruption reduces the rate of phagocytosis in cells, which is rescued by re-expression of VSK3. We found that the in vivo function of VSK3 depends on the presence of the kinase domain and vesicle localization. Furthermore, VSK3 is not essential for engulfment, but instead, is required for the fusion of phagosomes with late endosomes/lysosomes. Our findings suggest that localized tyrosine kinase signaling on the surface of endosome/lysosomes represents a control mechanism for phagosome maturation.

scholarly journals Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome: a rare association with high GGT level and absent kidney

2018 ◽  
pp. bcr-2017-223715
Author(s):  
Vishal Gupta ◽  
Aakash Pandita ◽  
Astha Panghal ◽  
Venkat Kallem
Keyword(s):  
Renal Dysfunction ◽  
Rare Association ◽  
Arc Syndrome

scholarly journals The VPS33B-binding protein VPS16B is required in megakaryocyte and platelet α-granule biogenesis

Blood ◽  
2012 ◽  
Vol 120 (25) ◽  
pp. 5032-5040 ◽  
Author(s):  
Denisa Urban ◽  
Ling Li ◽  
Hilary Christensen ◽  
Fred G. Pluthero ◽  
Shao Zun Chen ◽  
...  
Keyword(s):  
Immunofluorescence Microscopy ◽  
Binding Protein ◽  
Yeast Two Hybrid ◽  
Binding Partner ◽  
Late Endosomes ◽  
Arc Syndrome ◽  
Membrane Bound ◽  
Golgi Network ◽  
Two Hybrid

Abstract Patients with platelet α or dense δ-granule defects have bleeding problems. Although several proteins are known to be required for δ-granule development, less is known about α-granule biogenesis. Our previous work showed that the BEACH protein NBEAL2 and the Sec1/Munc18 protein VPS33B are required for α-granule biogenesis. Using a yeast two-hybrid screen, mass spectrometry, coimmunoprecipitation, and bioinformatics studies, we identified VPS16B as a VPS33B-binding protein. Immunoblotting confirmed VPS16B expression in various human tissues and cells including megakaryocytes and platelets, and also in megakaryocytic Dami cells. Characterization of platelets from a patient with arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome containing mutations in C14orf133 encoding VPS16B revealed pale-appearing platelets in blood films and electron microscopy revealed a complete absence of α-granules, whereas δ-granules were observed. Soluble and membrane-bound α-granule proteins were reduced or undetectable, suggesting that both releasable and membrane-bound α-granule constituents were absent. Immunofluorescence microscopy of Dami cells stably expressing GFP-VPS16B revealed that similar to VPS33B, GFP-VPS16B colocalized with markers of the trans-Golgi network, late endosomes and α-granules. We conclude that VPS16B, similar to its binding partner VPS33B, is essential for megakaryocyte and platelet α-granule biogenesis.

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