ANNIVERSARY
COMM
25thS

pecial Lectures ➋T

MEM165; a new key player inGolgi glycosylation andcellular Mn2+ homeostasis

François Foulquier

CNRS, UMR 8576, UGSF,
Unité de Glycobiologie Structurale et Fonctionnelle, University of Lille, France

François Foulquier is currently Research Director at CNRS institute in France (Centre National de la Recherche Scientifique). Dr. Foulquier received his PhD in Biochemistry at the University of Lille in 2003. From 2003-2007, he was a postdoctoral
Marie-Curie fellow at KU-Leuven (Belgium) with Pr. G. Matthijs. During his postdoc,
his research has focused on identifying and characterizing the molecular bases ofCongenital Disorders of Glycosylation (CDG) that are severe inherited diseases inwhich aberrant protein glycosylation is a hallmark. The discovery of genes not directly involved in the glycosylation process such as COGs/ TMEM165 let him toinvestigate the molecular mechanisms by which the regulation of the glycosylation
process at the ER/ Golgi levels occurs. Dr. Foulquier now runs a laboratory of 10 scientists at the Structural and Functional Glycobiology Unit (UGSF) in Lille. His current
work is aimed at understanding the impacts of vesicular trafficking, pH and Mn2+ ER/
Golgi homeostasis on the regulation of the glycosylation process. Additionally, Dr.
Foulquier was awarded the CNRS 2011 Bronze Medal for his contribution on CDG.
His work is currently supported by national (French National Agency) and europeangrants. He won Mizutani research grant in 2015.
​Congenital disorders of glycosylation (CDG) are severe inherited
diseases in which aberrant protein glycosylation is a hallmark.
From this genetically and clinically heterogenous group, a significant subgroup due to Golgi homeostasis defects is emerging. We
previously identified TMEM165 as a Golgi protein involved in CDG.
Extremely conserved in the eukaryotic reign, the molecular mechanism by which TMEM165 deficiencies lead to Golgi glycosylation
abnormalities was enigmatic. As GDT1 is the ortholog of TMEM165
in yeast, both gdt1Δ null mutant yeasts and TMEM165 depleted
cells were used. We highlighted that the observed Golgi glycosylation defects due to Gdt1p/TMEM165 deficiency result from Golgi
manganese homeostasis defect (Figure 1 panels A and B). We dis-44

the 25th Anniversary of Mizutani Foundation for Glycoscience

covered that in both yeasts and mammalian Gdt1p/TMEM165 deficient cells, Mn2+ supplementation could restore a normal glycosylation. We also showed that TMEM165 was a Mn2+ sensitive protein.
When exposed to high Mn2+ concentrations, we demonstrated thatTMEM165 was targeted and degraded in lysosomes. Remarkably,
the variant p.E108G recently identified in a novel TMEM165-CDG
patient, was found to be insensitive to Mn2+ supplementation. This
study not only provides novel insights into the molecular causes ofglycosylation defects observed in TMEM165-deficient cells but alsosuggests that TMEM165 is a key determinant for the regulation ofGolgi Mn2+ homeostasis (Figure 1).

MEMORATIVE SYMPOSIUM

Figure 1A	Proposed model for the function of TMEM165 in regulating Golgi together with the Ca2+/Mn2+ ATPase SPCA1. The Mn2+ concentration in theGolgi permits the Mn2+-dependent galactosyltransferases to transfer galactose residues from UDP-Gal to glycoconjugates.
B	Proposed model where TMEM165 is deficient. The lack of TMEM165 leads to a decreased Golgi level of Mn2+. The lack of Golgi Mn2+ impacts

the activity of Golgi galactosyltransferases and leads to the appearance of undergalactosylated glycoconjugates. Blue square: GlcNAc andyellow square: galactose.

Commemorative Symposium

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