Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3.

@article{Beers2013DisruptionON,
  title={Disruption of N-linked glycosylation promotes proteasomal degradation of the human ATP-binding cassette transporter ABCA3.},
  author={Michael F. Beers and Ming Zhao and Yaniv Tomer and Scott J. Russo and Peggy Zhang and Linda W. Gonzales and Susan H. Guttentag and Surafel Mulugeta},
  journal={American journal of physiology. Lung cellular and molecular physiology},
  year={2013},
  volume={305 12},
  pages={
          L970-80
        }
}
  • M. Beers, Ming Zhao, S. Mulugeta
  • Published 15 December 2013
  • Biology
  • American journal of physiology. Lung cellular and molecular physiology
The lipid transport protein, ABCA3, expressed in alveolar type 2 (AT2) cells, is critical for surfactant homeostasis. The first luminal loop of ABCA3 contains three putative N-linked glycosylation sites at residues 53, 124, and 140. A common cotranslational modification, N-linked glycosylation, is critical for the proper expression of glycoproteins by enhancing folding, trafficking, and stability through augmentation of the endoplasmic reticulum (ER) folding cycle. To understand its role in… 

Figures from this paper

Effect of N-glycosylation on the transport activity of the peptide transporter PEPT1.
TLDR
All glycosylation-deficient transporters were revealed to be functional with comparable expression levels in oocyte membranes except for the mutant protein N50Q, which exhibited a twofold decreased affinity for Gly-Sar but a 2.5-fold rise in the maximal inward currents compared with the wild-type protein.
Effect of N-Glycosylation on the Transport Activity of the Peptide 1 Transporter PEPT 1 2 3 4
TLDR
Two studies on mPEPT1 protein glycosylation and how glycans affect transport function are described and removal of the glycan at this location appears to accelerate the substrate turnover rate.
Analysis of the Proteolytic Processing of ABCA3: Identification of Cleavage Site and Involved Proteases
TLDR
It is shown that, like some other proteins of the lysosomal membrane, ABCA3 is a substrate of cathepsin L, which may represent a potential target to therapeutically influenceABCA3 activity in ABCA 3-associated lung disease.
N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) Determines Its Trafficking and Stability and Is Required for Hepatitis B Virus Infection
TLDR
N-glycosylation is required for efficient N TCP localization at the plasma membrane and subsequent HBV infection and these characteristics are preserved in NTCP carrying a single carbohydrate moiety.
Functional characterization of four ATP‐binding cassette transporter A3 gene (ABCA3) variants
ABCA3 transports phospholipids across lamellar body membranes in pulmonary alveolar type II cells and is required for surfactant assembly. Rare, biallelic, pathogenic ABCA3 variants result in lethal
The biology of the ABCA3 lipid transporter in lung health and disease
The lipid transporter, ATP-binding cassette class A3 (ABCA3), is a highly conserved multi-membrane-spanning protein that plays a critical role in the regulation of pulmonary surfactant homeostasis.
An N-Glycosylated Form of SERINC5 Is Specifically Incorporated into HIV-1 Virions
TLDR
It is shown that although not required for restrictive activity or Nef sensitivity, N-linked glycosylation is important for maintaining the steady-state expression of SERINC5 and that nonglycosylated SER INC5 is likely subjected to a quality control mechanism that induces its proteasomal degradation.
A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy.
TLDR
It is concluded that hSP-C(I73T) induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD.
GlycoMinestruct: a new bioinformatics tool for highly accurate mapping of the human N-linked and O-linked glycoproteomes by incorporating structural features
TLDR
GlycoMinestruct can be used as a powerful tool to expedite the discovery of glycosylation events and substrates to facilitate hypothesis-driven experimental studies and is proposed as a novel bioinformatics method for improved prediction of human N- and O-linked gly cosylation sites.
...
...

References

SHOWING 1-10 OF 63 REFERENCES
N-Linked glycosylation of the human ABC transporter ABCG2 on asparagine 596 is not essential for expression, transport activity, or trafficking to the plasma membrane.
TLDR
Immunoblot and pulse-chase analyses and site-directed mutagenesis experiments suggest that N-glycosylation at arginine 596 is not essential for the expression, trafficking to the plasma membrane, or the overall function of ABCG2.
Disruption of N‐linked glycosylation enhances ubiquitin‐mediated proteasomal degradation of the human ATP‐binding cassette transporter ABCG2
TLDR
It is proposed that the N‐linked glycan at Asn596 is important for stabilizing de’novo‐synthesized ABCG2 and that disruption of this linkage results in protein destabilization and enhanced ubiquitin‐mediated proteasomal degradation.
Glycosylation regulates the function and membrane localization of KCC4.
The Role of N-Linked Glycosylation in Protein Folding, Membrane Targeting, and Substrate Binding of Human Organic Anion Transporter hOAT4
TLDR
It is shown that both the disruption of the glycosylation sites by mutagenesis and the inhibition of glyCosylation by tunicamycin treatment resulted in a nonglycosylated hOAT4, which was unable to target to the cell surface.
N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic
TLDR
It is shown that N-glycans, specifically core glycans, enhance the productive folding and conformational stability of a polytopic membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR), independently of lectin-like chaperones.
Characterization and Classification of ATP-binding Cassette Transporter ABCA3 Mutants in Fatal Surfactant Deficiency*
TLDR
Intacellular localization and N-glycosylation of the ABCA3 mutants so far identified in fatal surfactant deficiency patients are investigated in HEK293 cells and mutational analyses of the Gly-1221 residue in the 11th transmembrane segment and the Leu-1580 residues in the cytoplasmic tail suggest a mechanism for impaired ATP hydrolysis in G1221S and L1580P mutants.
Regulation of the Stability of P-Glycoprotein by Ubiquitination
TLDR
It is shown that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance and suggests that modulating the ubiquitinated P- glycoprotein might be a novel approach to the reversal of drug resistance.
A novel conserved targeting motif found in ABCA transporters mediates trafficking to early post-Golgi compartments[S]
TLDR
A model whereby an N-terminal signal sequence, xLxxKN, directs ABCA transporters to a post-Golgi vesicular sorting station where additional signals may be required for selective delivery of individual transporter to final subcellular destinations is proposed.
Membrane Topology of the Multidrug Resistance Protein (MRP)
TLDR
N-Glycosylation of Asn19 and Asn23 provides the first direct experimental evidence that MRP has an extracytosolic NH2 terminus, and strongly suggests that the NH2-terminal MSD of MRP contains an odd number of transmembrane helices.
Functional and Trafficking Defects in ATP Binding Cassette A3 Mutants Associated with Respiratory Distress Syndrome*
TLDR
C cultured human lung cells found that recombinant wild-type hABCA3 localized to membranes of both lysosomes and lamellar bodies, which are the intracellular storage organelles for surfactant.
...
...