Home > Publications database > Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia. > print

001     295902
005     20250102093834.0
024 7 _ |a 10.1007/s00018-024-05506-7
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024 7 _ |a pmid:39680136
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024 7 _ |a 1420-682X
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024 7 _ |a 0014-4754
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024 7 _ |a 1420-9071
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024 7 _ |a altmetric:172170378
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037 _ _ |a DKFZ-2024-02716
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Kopp, Johannes
|0 0000-0002-0391-1497
|b 0
245 _ _ |a Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.
260 _ _ |a Cham (ZG)
|c 2025
|b Springer International Publishing AG
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a Loss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2-/-) and knock-in (Atp6v0a2RQ/RQ) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS. A hitherto unrecognized male infertility due to globozoospermia was evident in both mouse lines with impaired Golgi-derived acrosome formation and abolished mucin-type O-glycosylation in spermatids. Atp6v0a2-/- mutants showed enhanced fucosylation and glycosaminoglycan modification, but reduced levels of glycanated decorin and sialylation in skin and/or fibroblasts, which were absent or milder in Atp6v0a2RQ/RQ. Atp6v0a2RQ/RQ mutants displayed more abnormal migration of cortical neurons, correlating with seizures and a reduced O-mannosylation of α-dystroglycan. While anterograde transport within the secretory pathway was similarly delayed in both mutants the brefeldin A-induced retrograde fusion of Golgi membranes with the endoplasmic reticulum was less impaired in Atp6v0a2RQ/RQ. Measurement of the pH in the trans Golgi compartment revealed a shift from 5.80 in wildtype to 6.52 in Atp6v0a2-/- and 6.25 in Atp6v0a2RQ/RQ. Our findings suggest that altered O-glycosylation is more relevant for the WSS pathomechanism than N-glycosylation and leads to a secondary dystroglycanopathy. Most phenotypic and cellular properties correlate with the different degrees of trans Golgi pH elevation in both mutants underlining the fundamental relevance of pH regulation in the secretory pathway.
536 _ _ |a 311 - Zellbiologie und Tumorbiologie (POF4-311)
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650 _ 7 |a Cutis laxa
|2 Other
650 _ 7 |a Globozoospermia
|2 Other
650 _ 7 |a Glycosylation
|2 Other
650 _ 7 |a Golgi
|2 Other
650 _ 7 |a Neuronal migration
|2 Other
650 _ 7 |a Spermiogenesis
|2 Other
650 _ 7 |a V-ATPase
|2 Other
650 _ 7 |a Vesicular trafficking
|2 Other
650 _ 7 |a pH-regulation
|2 Other
650 _ 7 |a Vacuolar Proton-Translocating ATPases
|0 EC 3.6.1.-
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Glycosylation
|2 MeSH
650 _ 2 |a Golgi Apparatus: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Vacuolar Proton-Translocating ATPases: metabolism
|2 MeSH
650 _ 2 |a Vacuolar Proton-Translocating ATPases: genetics
|2 MeSH
650 _ 2 |a Hydrogen-Ion Concentration
|2 MeSH
650 _ 2 |a Mice, Knockout
|2 MeSH
650 _ 2 |a Teratozoospermia: metabolism
|2 MeSH
650 _ 2 |a Teratozoospermia: genetics
|2 MeSH
650 _ 2 |a Teratozoospermia: pathology
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Fibroblasts: metabolism
|2 MeSH
700 1 _ |a Jahn, Denise
|0 0000-0001-8912-5851
|b 1
700 1 _ |a Vogt, Guido
|0 0000-0002-7475-2972
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700 1 _ |a Psoma, Anthi
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700 1 _ |a Ratto, Edoardo
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700 1 _ |a Morelle, Willy
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700 1 _ |a Stelzer, Nina
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700 1 _ |a Hausser, Ingrid
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700 1 _ |a Hoffmann, Anne
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700 1 _ |a de Los Santos, Miguel Rodriguez
|0 0000-0002-2126-7658
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700 1 _ |a Koch, Leonard A
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700 1 _ |a Fischer-Zirnsak, Björn
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700 1 _ |a Thiel, Christian
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700 1 _ |a Palm, Wilhelm
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700 1 _ |a Meierhofer, David
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700 1 _ |a van den Bogaart, Geert
|0 0000-0003-2180-6735
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700 1 _ |a Foulquier, François
|0 0000-0001-5084-4015
|b 16
700 1 _ |a Meinhardt, Andreas
|0 0000-0003-3711-2746
|b 17
700 1 _ |a Kornak, Uwe
|0 0000-0002-4582-9838
|b 18
773 _ _ |a 10.1007/s00018-024-05506-7
|g Vol. 82, no. 1, p. 4
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|t Cellular and molecular life sciences
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|y 2025
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