Journal Article

DKFZ-2024-02716

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.

Kopp, J. ; Jahn, D. ; Vogt, G. ; Psoma, A. ; Ratto, E.DKFZ* ; Morelle, W. ; Stelzer, N. ; Hausser, I. ; Hoffmann, A. ; de Los Santos, M. R. ; Koch, L. A. ; Fischer-Zirnsak, B. ; Thiel, C. ; Palm, W.DKFZ* ; Meierhofer, D. ; van den Bogaart, G. ; Foulquier, F. ; Meinhardt, A. ; Kornak, U.

2025
Springer International Publishing AG Cham (ZG)

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Please use a persistent id in citations: doi:10.1007/s00018-024-05506-7

Abstract: 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.

Keyword(s): Animals (MeSH) ; Male (MeSH) ; Glycosylation (MeSH) ; Golgi Apparatus: metabolism (MeSH) ; Mice (MeSH) ; Vacuolar Proton-Translocating ATPases: metabolism (MeSH) ; Vacuolar Proton-Translocating ATPases: genetics (MeSH) ; Hydrogen-Ion Concentration (MeSH) ; Mice, Knockout (MeSH) ; Teratozoospermia: metabolism (MeSH) ; Teratozoospermia: genetics (MeSH) ; Teratozoospermia: pathology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Humans (MeSH) ; Fibroblasts: metabolism (MeSH) ; Cutis laxa ; Globozoospermia ; Glycosylation ; Golgi ; Neuronal migration ; Spermiogenesis ; V-ATPase ; Vesicular trafficking ; pH-regulation ; Vacuolar Proton-Translocating ATPases

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Contributing Institute(s):

1. A330 NWG Signaltransduktion und Stoffwechsel der Zelle (A330)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2024

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; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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