TY  - JOUR
AU  - Kopp, Johannes
AU  - Jahn, Denise
AU  - Vogt, Guido
AU  - Psoma, Anthi
AU  - Ratto, Edoardo
AU  - Morelle, Willy
AU  - Stelzer, Nina
AU  - Hausser, Ingrid
AU  - Hoffmann, Anne
AU  - de Los Santos, Miguel Rodriguez
AU  - Koch, Leonard A
AU  - Fischer-Zirnsak, Björn
AU  - Thiel, Christian
AU  - Palm, Wilhelm
AU  - Meierhofer, David
AU  - van den Bogaart, Geert
AU  - Foulquier, François
AU  - Meinhardt, Andreas
AU  - Kornak, Uwe
TI  - Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.
JO  - Cellular and molecular life sciences
VL  - 82
IS  - 1
SN  - 1420-682X
CY  - Cham (ZG)
PB  - Springer International Publishing AG
M1  - DKFZ-2024-02716
SP  - 4
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Male
KW  - Glycosylation
KW  - Golgi Apparatus: metabolism
KW  - Mice
KW  - Vacuolar Proton-Translocating ATPases: metabolism
KW  - Vacuolar Proton-Translocating ATPases: genetics
KW  - Hydrogen-Ion Concentration
KW  - Mice, Knockout
KW  - Teratozoospermia: metabolism
KW  - Teratozoospermia: genetics
KW  - Teratozoospermia: pathology
KW  - Mice, Inbred C57BL
KW  - Humans
KW  - Fibroblasts: metabolism
KW  - Cutis laxa (Other)
KW  - Globozoospermia (Other)
KW  - Glycosylation (Other)
KW  - Golgi (Other)
KW  - Neuronal migration (Other)
KW  - Spermiogenesis (Other)
KW  - V-ATPase (Other)
KW  - Vesicular trafficking (Other)
KW  - pH-regulation (Other)
KW  - Vacuolar Proton-Translocating ATPases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39680136
DO  - DOI:10.1007/s00018-024-05506-7
UR  - https://inrepo02.dkfz.de/record/295902
ER  -