The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility

Spliid, Charlotte B.; Toledo, Alejandro Gómez; Sanderson, Patience; Mao, Yang; Gatto, Francesco; Gustavsson, Tobias; Choudhary, Swati; Saldanha, Ana L.; Vogelsang, Rasmus Peuliche; Gögenür, Ismail; Theander, Thor G.; Leach, Franklin E.; Amster, I. Jonathan; Salanti, Ali; Clausen, Thomas

doi:10.1016/j.jbc.2021.101391

Cited by 12 publications

(13 citation statements)

References 61 publications

(100 reference statements)

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“…The treatment of human cerebrovascular cells, placental cells, and bronchial epithelial cystic fibrosis cells, corrected or uncorrected for CFTR, by chloroquine (50 nM × 24 h), significantly reduced the ARSB activity, protein, and mRNA [ 44 ]. This finding is relevant to multiple studies which demonstrate that more highly sulfated chondroitin 4-sulfate reduces infectivity by malarial parasites [ 76 , 77 , 78 , 79 ].…”

Section: Inhibition Of Arsb Activity By Ions Metals Hormones Chemical...mentioning

confidence: 61%

“…These residues, which are distinct in SHP2, may act to stabilize the anionic sulfate of C4S and maintain SHP2 in a bound, inactive conformation. The 4-sulfate group at the non-reducing end of C4S may be a unique configuration; it has previously been shown to be critically important in binding of malarial parasites in the vasculature [ 76 , 77 , 78 , 79 ]. Thus, the retained 4-sulfate group at the non-reducing end of C4S when ARSB is reduced may provide a niche for SHP2 interaction, leading to SHP2 inactivation, and sustained activation of ERK1/2 [ 33 , 36 ], JNK [ 28 ], and p38-MAPK [ 14 , 38 ] and thereby impact on critical intracellular signaling pathways.…”

Section: Arylsulfatase B and Chondroitin 4-sulfation Regulate Signali...mentioning

confidence: 99%

“…Publications have suggested that CF carrier advantage status may provide protection from tuberculosis and malaria [ 159 , 160 ]. Decline in ARSB and change in chondroitin sulfation have been considered in relationship to protection from these diseases [ 76 , 77 , 78 , 79 , 97 ].…”

Section: Diseases With Deficiency Of Arylsulfatase Bmentioning

confidence: 99%

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Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Tobacman

Bhattacharyya

2022

IJMS

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The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.

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Section: Inhibition Of Arsb Activity By Ions Metals Hormones Chemical...mentioning

confidence: 61%

Section: Arylsulfatase B and Chondroitin 4-sulfation Regulate Signali...mentioning

confidence: 99%

See 1 more Smart Citation

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Tobacman

Bhattacharyya

2022

IJMS

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“…By frontal affinity chromatography, the β-galactoside binding proteins galectins 3, 7, and 9 were shown to bind preferentially to desulfated galactosaminoglycans, rather than more highly sulfated C4S or DS [75]. When ARSB was silenced and chondroitin 4-sulfation thereby increased, galectin-3 binding with C4S declined and nuclear galectin-3 increased in human prostate epithelial and stromal cells, human colonic cell lines, and control and ARSB-null mouse colonic epithelium, and human bronchial epithelial cells [26,31].…”

Section: Activation Of Galectin-3 (Lgals3)mentioning

confidence: 99%

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Tobacman¹,

Bhattacharyya²

2022

Preprint

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The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). Newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. Regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.

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“…These parasites express a surface ligand that is unique to placental malaria called VAR2CSA. VAR2CSA is a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and binds to chondroitin sulfate A (CSA), a glycosaminoglycan found in the placenta and other cells that mediates sequestration of iRBCs in pregnancy-associated malaria (PAM) (10,11). These parasites bind to CSA but not to other major surface ligands, notably CD36 and ICAM-1, whereas most parasite isolates from nonpregnant women do the contrary (12, 13).…”

Section: Immunopathogenesis Of Malaria In Pregnancymentioning

confidence: 99%

Towards identification and development of alternative vaccines against pregnancy-associated malaria based on naturally acquired immunity

Rotich¹,

Takashima²,

Yanow³

et al. 2022

Front. Trop. Dis

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Pregnant women are particularly susceptible to Plasmodium falciparum malaria, leading to substantial maternal and infant morbidity and mortality. While highly effective malaria vaccines are considered an essential component towards malaria elimination, strides towards development of vaccines for pregnant women have been minimal. The leading malaria vaccine, RTS,S/AS01, has modest efficacy in children suggesting that it needs to be strengthened and optimized if it is to be beneficial for pregnant women. Clinical trials against pregnancy-associated malaria (PAM) focused on the classical VAR2CSA antigen are ongoing. However, additional antigens have not been identified to supplement these initiatives despite the new evidence that VAR2CSA is not the only molecule involved in pregnancy-associated naturally acquired immunity. This is mainly due to a lack of understanding of the immune complexities in pregnancy coupled with difficulties associated with expression of malaria recombinant proteins, low antigen immunogenicity in humans, and the anticipated complications in conducting and implementing a vaccine to protect pregnant women. With the accelerated evolution of molecular technologies catapulted by the global pandemic, identification of novel alternative vaccine antigens is timely and feasible. In this review, we discuss approaches towards novel antigen discovery to support PAM vaccine studies.

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The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility

Cited by 12 publications

References 61 publications

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases

Towards identification and development of alternative vaccines against pregnancy-associated malaria based on naturally acquired immunity

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