Wilson disease-causing mutations in the carboxyl terminus of ATP7B regulates its localization and Golgi exit selectively in the unpolarized cells

被引:0
作者
Chakraborty, Kaustav [1 ,2 ]
Das, Santanu
Pal, Anusree [1 ,2 ]
Maji, Saptarshi
Rai, Bhawana [1 ,2 ]
Gupta, Arnab
Bhattacharjee, Ashima [1 ,2 ]
机构
[1] Amity Univ, Amity Inst Biotechnol, Kolkata, India
[2] Indian Inst Sci Educ & Res, Dept Biol Sci, Kolkata, India
基金
英国惠康基金;
关键词
ATP7B; differentiated glia; mutation; polarized; Wilson disease; COPPER TRANSPORTER; MOLECULAR DIAGNOSIS; ATPASE ATP7B; PROTEIN; PHENOTYPE; IDENTIFICATION; GENOTYPE; GENE;
D O I
10.1093/mtomcs/mfad051
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutational inactivation of the P-type Cu-ATPase ATP7B interferes with its cellular functions to varying extent leading to varied cellular phenotypes. Wilson's disease (WD) primarily affects organs composed of polarized/differentiated epithelial cells. Therefore, phenotypic variability might differ depending on the polarization/differentiation of the cells. The present study investigates the intracellular stability and localization of ATP7B harboring WD mutations in both unpolarized/undifferentiated and polarized/differentiated cell-based models. Green fluorescent protein (GFP)-ATP7B harboring the WD causing mutations, N41S, S653Y, R778Q, G1061E, H1069Q, S1423N, S1426I, and T1434M, are included for investigation. The C-terminal WD mutations (S1423N, S1426I, and T1434M), exhibit distinct localization and Cu(I) responsive anterograde and retrograde trafficking in undifferentiated/unpolarized vs. differentiated/polarized cells. While basal localization of the S1423N mutant gets corrected in the differentiated glia, its Cu(I) responsive anterograde and retrograde trafficking behavior is not identical to the wild-type. But localization and trafficking properties are completely rescued for the S1426I and T1434M mutants in the differentiated cells. Comprehensive meta-analysis on the effect of the reported C-terminal mutations on patient phenotype and cultured cells demonstrate discrete regions having distinct effects. While mutations in the proximal C-terminus affect ATP7B stability, the present study shows that the distal region dictates cell-specific Trans Golgi Network (TGN) localization and exit. The localization and export properties are corrected in the differentiated cells, which is a plausible mechanism for the milder phenotype exhibited by these mutations. It highlights the critical role of the C-terminus in cell-specific TGN retention and exit of ATP7B.
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页数:19
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