Pluripotent stem cell-derived bile canaliculi-forming hepatocytes to study genetic liver diseases involving hepatocyte polarity

Overeem, Arend W.; Klappe, Karin; Parisi, Silvia; Klöters-Planchy, Petra; Matakovic, Lavinija; Espina, Marines du Teil; Drouin, Christian A.; Weiss, Karl Heinz; IJzendoorn, Sven C. D. van

doi:10.1016/j.jhep.2019.03.031

Cited by 30 publications

(33 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the disruption of ATP7B interaction with AP1 in either WD or MEDNIK syndrome may direct ATP7B to the wrong compartment along the endocytic pathway, where ATP7B would be unable to regulate copper balance in the cell. Surprisingly, a recent study in hepatocyte‐like cells from MEDNIK patients did not reveal any evident alteration in the localization and trafficking of ATP7B . Therefore, the impact of the AP1S1 mutations on ATP7B sorting and targeting and corresponding changes in the intracellular Cu distribution has yet to be fully understood.…”

Section: Atp7b Retrieval To the Golgimentioning

confidence: 92%

“…The identity of the ATP7B vesicles is an ongoing debate. Recent studies in hepatic HepG2 cells, in human hepatocytes and in mouse liver tissue indicate that ATP7B vesicles belong to the late endosomal (LE)/lysosomal compartments [21,33,34]. In contrast, other reports suggest that ATP7B moves from the Golgi to early endosomes in Can10 and WIF-B hepatic cells [35,36].…”

Section: Atp7b 'Vesicles'mentioning

confidence: 98%

“…Several lines of evidence strengthen the notion of Cu-dependent delivery of ATP7B to LEs/lysosomes. Firstly, significant overlap of endogenous ATP7B with LE/lysosomal markers was recently documented in different hepatic cell lines, including polarized cells [21,33,34,39]. Secondly, electron microscopy studies in different hepatic cell lines revealed endogenous or GFP-tagged ATP7B within relatively large vacuolar structures whose ultrastructural features resemble LEs/lysosomes due to the presence of intraluminal vesicles and/or heterogeneous electron dense material [21,33].…”

Section: Atp7b 'Vesicles'mentioning

confidence: 99%

“…In this context, it is important to understand which hepatic cell type better recapitulates ATP7B localization/trafficking in liver tissue. Given that ATP7B was detected in LEs/lysosomes in both liver tissue and human hepatocytes , ATP7B targeting to LEs/lysosomes in HepG2 cells argues in favor of these cell types rather than WIF‐B or Can10 cells as a suitable model for ATP7B trafficking studies.…”

Section: Atp7b ‘Vesicles’mentioning

confidence: 99%

“…However, it is always important to keep in mind that despite the similarity, ATP7A and ATP7B are frequently directed to different cellular destinations and thus might employ different trafficking pathways and machineries. For example, AP1S1 deficiency in MEDNIK syndrome affects ATP7A localization but apparently does not impair trafficking of ATP7B . Thus, it remains to be formally demonstrated that ATP7B uses the COG‐, retromer‐, BLOC‐1‐, WASH‐ and CCC‐dependent routes, which all operate in ATP7A trafficking .…”

Section: Future Perspectives and Challengesmentioning

confidence: 99%

See 4 more Smart Citations

From and to the Golgi – defining the Wilson disease protein road map

Polishchuk

2019

FEBS Letters

View full text Add to dashboard Cite

Recent studies highlight the continued growth in the identification of a variety of cellular functions that involve the Golgi apparatus. Apart from well‐known membrane sorting/trafficking and glycosylation machineries, the Golgi harbors molecular platforms operating in intracellular signaling, cytoskeleton organization, and protein quality control mechanisms. One of new emerging Golgi functions consists in the regulation of copper homeostasis by coordinating the relocation and activity of copper transporters. Of these, the Cu‐transporting ATPase ATP7B (known as Wilson disease protein) plays a key role in the maintenance of the Cu balance in the body via the supply of essential Cu to the systemic circulation and via elimination of excess Cu into the bile. These activities require tightly regulated shuttling of ATP7B between the Golgi and different post‐Golgi compartments. Despite significant progress over recent years, a number of issues regarding ATP7B trafficking remain to be clarified. This review summarizes current views on ATP7B trafficking pathways from and to the Golgi and underscores the challenges that should be addressed to define the ATP7B trafficking routes and mechanisms in health and disease.

show abstract

Section: Atp7b Retrieval To the Golgimentioning

confidence: 92%

Section: Atp7b 'Vesicles'mentioning

confidence: 98%

Section: Atp7b 'Vesicles'mentioning

confidence: 99%

Section: Atp7b ‘Vesicles’mentioning

confidence: 99%

Section: Future Perspectives and Challengesmentioning

confidence: 99%

See 3 more Smart Citations

From and to the Golgi – defining the Wilson disease protein road map

Polishchuk

2019

FEBS Letters

View full text Add to dashboard Cite

show abstract

A Molecular Mechanism Underlying Genotype‐Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations

Overeem

Qiu

et al. 2020

Hepatology

Self Cite

View full text Add to dashboard Cite

Background and Aims Progressive familial intrahepatic cholestasis (PFIC) 6 has been associated with missense but not biallelic nonsense or frameshift mutations in MYO5B , encoding the motor protein myosin Vb (myoVb). This genotype‐phenotype correlation and the mechanism through which MYO5B mutations give rise to PFIC are not understood. The aim of this study was to determine whether the loss of myoVb or expression of patient‐specific myoVb mutants can be causally related to defects in canalicular protein localization and, if so, through which mechanism. Approach and Results We demonstrate that the cholestasis‐associated substitution of the proline at amino acid position 600 in the myoVb protein to a leucine (P660L) caused the intracellular accumulation of bile canalicular proteins in vesicular compartments. Remarkably, the knockout of MYO5B in vitro and in vivo produced no canalicular localization defects. In contrast, the expression of myoVb mutants consisting of only the tail domain phenocopied the effects of the Myo5b‐P660L mutation. Using additional myoVb and rab11a mutants, we demonstrate that motor domain‐deficient myoVb inhibited the formation of specialized apical recycling endosomes and that its disrupting effect on the localization of canalicular proteins was dependent on its interaction with active rab11a and occurred at the trans ‐Golgi Network/recycling endosome interface. Conclusions Our results reveal a mechanism through which MYO5B motor domain mutations can cause the mislocalization of canalicular proteins in hepatocytes which, unexpectedly, does not involve myoVb loss‐of‐function but, as we propose, a rab11a‐mediated gain‐of‐toxic function. The results explain why biallelic MYO5B mutations that affect the motor domain but not those that eliminate myoVb expression are associated with PFIC6.

show abstract

Unequal Effects of Myosin 5B Mutations in Liver and Intestine Determine the Clinical Presentation of Low‐Gamma‐Glutamyltransferase Cholestasis

IJzendoorn

Qiu

et al. 2020

Hepatology

Self Cite

View full text Add to dashboard Cite

Myosin 5B-Associated Cholestatic Liver Disease Cholestatic liver disease (CLD) is characterized by an increase in the serum concentrations of compounds that are normally excreted with bile, such as bile acids and bilirubin. (1) CLD clinically manifest with cholestasis, jaundice, and pruritis. Diagnosis involves evaluation of the patient's clinical manifestations, exclusion of common causes of childhood cholestasis, and analyses of blood biochemistry and liver histology. (1) One blood marker that aids in the differential diagnosis of liver diseases is gamma-glutamyltransferase (GGT), a liver enzyme which is typically elevated in serum upon liver damage. The best known CLDs characterized by low/normal GGT are the benign recurrent and progressive forms of familial intrahepatic cholestasis (BRIC/PFIC), which are caused by mutations in the adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) gene encoding the ATP8B1 protein (BRIC/PFIC1) or in the adenosine triphosphate-binding cassette family B member 11 (ABCB11) gene encoding the canalicular bile salt export pump (BSEP) (BRIC/PFIC2). (2,3) In hepatocytes, ATP8B1 and BSEP are localized to the apical bile canalicular domain, where they contribute to biliary secretion. When mutated as in PFIC1/2 patients, the respective proteins are less expressed or mislocalized and/or display impaired activity, leading to defective biliary secretion and, consequently, cholestasis. (2,3) Since 2017 four independent reports have identified in total 30 different myosin 5B (MYO5B) mutations in 22 patients with non-microvillus inclusion disease (MVID) who were diagnosed with intermittent, recurrent, or progressive cholestasis presenting with jaundice, pruritus, hepatomegaly, and low/normal serum levels of GGT (Fig. 1; Supporting Table S1). These patients tested negative for mutations in other PFIC-associated genes. (4-7) MYO5B mutations may account for approximately 20% of pediatric patients with idiopathic low-GGT intrahepatic cholestasis. (8)

show abstract

Pluripotent stem cell-derived bile canaliculi-forming hepatocytes to study genetic liver diseases involving hepatocyte polarity

Cited by 30 publications

References 46 publications

From and to the Golgi – defining the Wilson disease protein road map

From and to the Golgi – defining the Wilson disease protein road map

A Molecular Mechanism Underlying Genotype‐Specific Intrahepatic Cholestasis Resulting From MYO5B Mutations

Unequal Effects of Myosin 5B Mutations in Liver and Intestine Determine the Clinical Presentation of Low‐Gamma‐Glutamyltransferase Cholestasis

Contact Info

Product

Resources

About