Differential Effects of D-Galactose Supplementation on Golgi Glycosylation Defects in TMEM165 Deficiency

Zoé Durin; Marine Houdou; Willy Morelle; Lydia Barré; Aurore Layotte; Dominique Legrand; Mohamed Ouzzine; François Foulquier

doi:10.3389/fcell.2022.903953

Differential Effects of D-Galactose Supplementation on Golgi Glycosylation Defects in TMEM165 Deficiency

Front Cell Dev Biol. 2022 May 26:10:903953. doi: 10.3389/fcell.2022.903953. eCollection 2022.

Authors

Zoé Durin¹, Marine Houdou¹, Willy Morelle¹, Lydia Barré², Aurore Layotte¹, Dominique Legrand¹, Mohamed Ouzzine², François Foulquier¹

Affiliations

¹ University of Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France.
² Faculty of Medicine, UMR7365 CNRS-University of Lorraine, Biopôle, Nancy, France.

Abstract

Glycosylation is a ubiquitous and universal cellular process in all domains of life. In eukaryotes, many glycosylation pathways occur simultaneously onto proteins and lipids for generating a complex diversity of glycan structures. In humans, severe genetic diseases called Congenital Disorders of Glycosylation (CDG), resulting from glycosylation defects, demonstrate the functional relevance of these processes. No real cure exists so far, but oral administration of specific monosaccharides to bypass the metabolic defects has been used in few CDG, then constituting the simplest and safest treatments. Oral D-Galactose (Gal) therapy was seen as a promising tailored treatment for specific CDG and peculiarly for TMEM165-CDG patients. TMEM165 deficiency not only affects the N-glycosylation process but all the other Golgi-related glycosylation types, then contributing to the singularity of this defect. Our previous results established a link between TMEM165 deficiency and altered Golgi manganese (Mn²⁺) homeostasis. Besides the fascinating power of MnCl₂ supplementation to rescue N-glycosylation in TMEM165-deficient cells, D-Gal supplementation has also been shown to be promising in suppressing the observed N-glycosylation defects. Its effect on the other Golgi glycosylation types, most especially O-glycosylation and glycosaminoglycan (GAG) synthesis, was however unknown. In the present study, we demonstrate the differential impact of D-Gal or MnCl₂ supplementation effects on the Golgi glycosylation defects caused by TMEM165 deficiency. Whereas MnCl₂ supplementation unambiguously fully rescues the N- and O-linked as well as GAG glycosylations in TMEM165-deficient cells, D-Gal supplementation only rescues the N-linked glycosylation, without any effects on the other Golgi-related glycosylation types. According to these results, we would recommend the use of MnCl₂ for TMEM165-CDG therapy.

Keywords: CDG; TMEM165-CDG; galactose; glycosylation; manganese.