Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Braiterman, Lelita T.; Murthy, Amrutha; Jayakanthan, Samuel; Nyasae, Lydia; Tzeng, Eric; Gromadzka, Grażyna; Woolf, Thomas B.; Lutsenko, Svetlana; Hubbard, Ann L.

doi:10.1073/pnas.1314161111

Cited by 41 publications

(43 citation statements)

References 68 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This, in turn, may disrupt the homeostatic Cu balance, resulting in Cu deficiency (Menkes disease) or Cu overload (Wilson disease). Wilson disease (WD) is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in the trans -Golgi network (TGN) and exports excess copper by trafficking from the TGN to the plasma membrane (Braiterman et al, 2014). While these studies have yielded a better insight into the enzymatic properties and cell biology of the Cu ATPases, the mechanism by which the Golgi regulates trafficking of ATP7A/7B and, thereby, maintains Cu homeostasis remains unclear.…”

Section: Cu Homeostasismentioning

confidence: 99%

Copper: toxicological relevance and mechanisms

2014

View full text Add to dashboard Cite

Copper (Cu) is a vital mineral essential for many biological processes. The vast majority of all Cu in healthy humans is associated with enzyme prosthetic groups or bound to proteins. Cu homeostasis is tightly regulated through a complex system of Cu transporters and chaperone proteins. Excess or toxicity of Cu, which is associated with the pathogenesis of hepatic disorder, neurodegenerative changes and other disease conditions, can occur when Cu homeostasis is disrupted. The capacity to initiate oxidative damage is most commonly attributed to Cu-induced cellular toxicity. Recently, altered cellular events, including lipid metabolism, gene expression, alpha-synuclein aggregation, activation of acidic sphingomyelinase and release of ceramide, and temporal and spatial distribution of Cu in hepatocytes, as well as Cu-protein interaction in the nerve system, have been suggested to play a role in Cu toxicity. However, whether these changes are independent of, or secondary to, an altered cellular redox state of Cu remain to be elucidated.

show abstract

Section: Cu Homeostasismentioning

confidence: 99%

Copper: toxicological relevance and mechanisms

2014

View full text Add to dashboard Cite

show abstract

“…These various mutations decrease ATP7B levels, cause improper protein localization, and reduce substrate binding (copper, ATP) and activity. 24–26 …”

Section: Genetics Of Wilson Diseasementioning

confidence: 99%

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Kieffer

Medici

2017

Liver Research

View full text Add to dashboard Cite

Environmental factors, including diet, exercise, stress, and toxins, profoundly impact disease phenotypes. This review examines how Wilson disease (WD), an autosomal recessive genetic disorder, is influenced by genetic and environmental inputs. WD is caused by mutations in the copper-transporter gene ATP7B, leading to the accumulation of copper in the liver and brain, resulting in hepatic, neurological, and psychiatric symptoms. These symptoms range in severity and can first appear anytime between early childhood and old age. Over 300 disease-causing mutations in ATP7B have been identified, but attempts to link genotype to the phenotypic presentation have yielded little insight, prompting investigators to identify alternative mechanisms, such as epigenetics, to explain the highly varied clinical presentation. Further, WD is accompanied by structural and functional abnormalities in mitochondria, potentially altering the production of metabolites that are required for epigenetic regulation of gene expression. Notably, environmental exposure affects the regulation of gene expression and mitochondrial function. We present the “multi-hit” hypothesis of WD progression, which posits that the initial hit is an environmental factor that affects fetal gene expression and epigenetic mechanisms and subsequent “hits” are environmental exposures that occur in the offspring after birth. These environmental hits and subsequent changes in epigenetic regulation may impact copper accumulation and ultimately WD phenotype. Lifestyle changes, including diet, increased physical activity, stress reduction, and toxin avoidance, might influence the presentation and course of WD, and therefore may serve as potential adjunctive or replacement therapies.

show abstract

“…The trafficking mechanisms that operate physiologically during Cu‐directed trafficking of ATP7B in hepatocytes remain poorly understood. We recently identified a Wilson's disease mutation that affects the intracellular trafficking of ATP7B, while having little effect on ATPase activity itself, indicating that a mislocalization of ATP7B is sufficient to cause Wilson's disease .…”

mentioning

confidence: 99%

Copper Directs ATP7B to the Apical Domain of Hepatic Cells via Basolateral Endosomes

Nyasae¹,

Schell²,

Hubbard³

2014

Traffic

Self Cite

View full text Add to dashboard Cite

Physiologic Cu levels regulate the intracellular location of the Cu ATPase ATP7B. Here, we determined the routes of Cu-directed trafficking of endogenous ATP7B in the polarized hepatic cell line WIF-B and in the liver in vivo. Copper (10 μM) caused ATP7B to exit the trans-Golgi network (TGN) in vesicles, which trafficked via large basolateral endosomes to the apical domain within one hour. Although perturbants of luminal acidification had little effect on the TGN localization of ATP7B in low Cu, they blocked delivery to the apical membrane in elevated Cu. If the vesicular proton-pump inhibitor bafilomycin-A1 (Baf) was present with Cu, ATP7B still exited the TGN, but accumulated in large endosomes located near the coverslip, in the basolateral region. Baf washout restored ATP7B trafficking to the apical domain. If ATP7B was staged apically in high Cu, Baf addition promoted the accumulation of ATP7B in subapical endosomes, indicating a blockade of apical recycling, with concomitant loss of ATP7B at the apical membrane. The retrograde pathway to the TGN, induced by Cu removal, was far less affected by Baf than the anterograde (Cu-stimulated) case. Overall, loss of acidification impaired Cu-regulated trafficking of ATP7B at two main sites: 1) sorting and exit from large basolateral endosomes and 2) recycling via endosomes near the apical membrane.

show abstract

Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Cited by 41 publications

References 68 publications

Copper: toxicological relevance and mechanisms

Copper: toxicological relevance and mechanisms

Wilson disease: At the crossroads between genetics and epigenetics—A review of the evidence

Copper Directs ATP7B to the Apical Domain of Hepatic Cells via Basolateral Endosomes

Contact Info

Product

Resources

About