Zhantao Yang

Publications (5)74.73 Total impact

• Article: Kinetics and specificity of feline leukemia virus subgroup C receptor (FLVCR) export function and its dependence on hemopexin.

  Zhantao Yang, John D Philips, Raymond T Doty, Pablo Giraudi, J Donald Ostrow, Claudio Tiribelli, Ann Smith, Janis L Abkowitz
  [show abstract] [hide abstract]
  ABSTRACT: The feline leukemia virus subgroup C receptor (FLVCR) is a heme export protein that is required for proerythroblast survival and facilitates macrophage heme iron recycling. However, its mechanism of heme export and substrate specificity are uncharacterized. Using [(55)Fe]heme and the fluorescent heme analog zinc mesoporphyrin, we investigated whether export by FLVCR depends on the availability and avidity of extracellular heme-binding proteins. Export was 100-fold more efficient when the medium contained hemopexin (K(d) < 1 pm) compared with albumin (K(d) = 5 nm) at the same concentration and was not detectable when the medium lacked heme-binding proteins. Besides heme, FLVCR could export other cyclic planar porphyrins, such as protoporphyrin IX and coproporphyrin. However, FLVCR has a narrow substrate range because unconjugated bilirubin, the primary breakdown product of heme, was not transported. As neither protoporphyrin IX nor coproporphyrin export improved with extracellular hemopexin (versus albumin), our observations further suggest that hemopexin, an abundant protein with a serum concentration (6.7-25 mum) equivalent to that of the iron transport protein transferrin (22-31 mum), by accepting heme from FLVCR and targeting it to the liver, might regulate macrophage heme export and heme iron recycling in vivo. Final studies show that hemopexin directly interacts with FLVCR, which also helps explain why FLVCR, in contrast to some major facilitator superfamily members, does not function as a bidirectional gradient-dependent transporter. Together, these data argue that hemopexin has a role in assuring systemic iron balance during homeostasis in addition to its established role as a scavenger during internal bleeding or hemolysis.
  Journal of Biological Chemistry 09/2010; 285(37):28874-82. · 4.77 Impact Factor
• Article: In utero transplantation of monocytic cells in cats with alpha-mannosidosis.

  Janis L Abkowitz, Kathleen M Sabo, Zhantao Yang, Charles H Vite, Laurence E Shields, Mark E Haskins
  [show abstract] [hide abstract]
  ABSTRACT: Lysosomal storage diseases are devastating illnesses, in large part because of their neurologic consequences. Because significant morbidity occurs prenatally, in utero (IU) therapy is an attractive therapeutic approach. We studied the feasibility and efficacy of IU injections of monocytic cells (derived from normal marrow) in feline alpha-mannosidosis. Heterozygous cats were interbred to produce affected (homozygous) and control (heterozygous and wild-type) offspring. Thirty-seven pregnancies were studied in which fetuses were transplanted intraperitoneally (1x10 cells/kg recipient) at gestational days 27 to 33 and then each week for 2 weeks (term=63 days). After birth, affected kittens were evaluated clinically and pathologically, tissue alpha-mannosidase levels were assayed, and in many studies, the numbers of alpha-mannosidase-containing cells were enumerated. When male donor cells were transplanted into female recipients, engraftment was also quantified using polymerase chain reaction to amplify a Y chromosome-specific sequence. We establish methods to transplant cats intraperitoneally while IU using ultrasound guidance, thus, describing a new large animal model for prenatal therapy. We show that the donor monocytic cells engraft and persist (for up to 125 days) in the brain, liver, and spleen, albeit at levels below those needed to alter the clinical or pathological progression of the alpha-mannosidosis. This is the first study of monocyte transplantation in a large animal model of a lysosomal storage disorder and demonstrates its feasibility, safety, and promise. Delivering cells IU may be a useful strategy to prevent morbidities before a definitive therapy, such as hematopoietic stem-cell transplantation, can be administered after birth.
  Transplantation 09/2009; 88(3):323-9. · 4.00 Impact Factor
• Article: A heme export protein is required for red blood cell differentiation and iron homeostasis.

  Siobán B Keel, Raymond T Doty, Zhantao Yang, John G Quigley, Jing Chen, Sue Knoblaugh, Paul D Kingsley, Ivana De Domenico, Michael B Vaughn, Jerry Kaplan, James Palis, Janis L Abkowitz
  [show abstract] [hide abstract]
  ABSTRACT: Hemoproteins are critical for the function and integrity of aerobic cells. However, free heme is toxic. Therefore, cells must balance heme synthesis with its use. We previously demonstrated that the feline leukemia virus, subgroup C, receptor (FLVCR) exports cytoplasmic heme. Here, we show that FLVCR-null mice lack definitive erythropoiesis, have craniofacial and limb deformities resembling those of patients with Diamond-Blackfan anemia, and die in midgestation. Mice with FLVCR that is deleted neonatally develop a severe macrocytic anemia with proerythroblast maturation arrest, which suggests that erythroid precursors export excess heme to ensure survival. We further demonstrate that FLVCR mediates heme export from macrophages that ingest senescent red cells and regulates hepatic iron. Thus, the trafficking of heme, and not just elemental iron, facilitates erythropoiesis and systemic iron balance.
  Science 03/2008; 319(5864):825-8. · 31.20 Impact Factor
• Source

  Available from: washington.edu

  Article: Identification of a human heme exporter that is essential for erythropoiesis.

  John G Quigley, Zhantao Yang, Mark T Worthington, John D Phillips, Kathleen M Sabo, Daniel E Sabath, Carl L Berg, Shigeru Sassa, Brent L Wood, Janis L Abkowitz
  [show abstract] [hide abstract]
  ABSTRACT: FLVCR, a member of the major facilitator superfamily of transporter proteins, is the cell surface receptor for feline leukemia virus, subgroup C. Retroviral interference with FLVCR display results in a loss of erythroid progenitors (colony-forming units-erythroid, CFU-E) and severe anemia in cats. In this report, we demonstrate that human FLVCR exports cytoplasmic heme and hypothesize that human FLVCR is required on developing erythroid cells to protect them from heme toxicity. Inhibition of FLVCR in K562 cells decreases heme export, impairs their erythroid maturation and leads to apoptosis. FLVCR is upregulated on CFU-E, indicating that heme export is important in primary cells at this stage. Studies of FLVCR expression in cell lines suggest this exporter also impacts heme trafficking in intestine and liver. To our knowledge, this is the first description of a mammalian heme transporter.
  Cell 10/2004; 118(6):757-66. · 32.40 Impact Factor
• Article: Investigation of a putative role for FLVCR, a cytoplasmic heme exporter, in Diamond-Blackfan anemia.

  John G Quigley, Hanna Gazda, Zhantao Yang, Sarah Ball, Colin A Sieff, Janis L Abkowitz
  [show abstract] [hide abstract]
  ABSTRACT: Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia. Previous studies indicate that mutations of a gene on chromosome 19q13.2, which encodes a ribosomal protein, are responsible for 25% of cases. Recent investigations suggest both the presence of a second candidate region on chromosome 8p and non-19q, non-8p disease. In linkage analysis studies of 28 multiplex DBA families, we identified 8 families with disease linkage to chromosome 1q31. In 4 families, the disease linked exclusively to 1q31. Here, we report that the FLVCR gene on 1q31, which encodes a cytoplasmic heme exporter associated with red cell aplasia in cats, is not involved in DBA in these families.
  Blood Cells Molecules and Diseases 35(2):189-92. · 2.35 Impact Factor