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Dissection of TMEM165 function in Golgi glycosylation and its Mn2+ sensitivity

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Lebredonchel, Elodie | Houdou, Marine | Potelle, Sven | de Bettignies, Geoffroy | Schulz, Céline | Krzewinski Recchi, Marie-Ange | Lupashin, Vladimir | Legrand, Dominique | Klein, André | Foulquier, François

Edité par CCSD ; Elsevier -

International audience. Since 2012, the interest for TMEM165 increased due to its implication in a rare genetic human disease named TMEM165-CDG (Congenital Disorder(s) of Glycosylation). TMEM165 is a Golgi localized protein, highly conserved through evolution and belonging to the uncharacterized protein family 0016 (UPF0016). Although the precise function of TMEM165 in glycosylation is still controversial, our results highly suggest that TMEM165 would act as a Golgi Ca 2þ /Mn 2þ transporter regulating both Ca 2þ and Mn 2þ Golgi homeostasis, the latter is required as a major cofactor of many Golgi glycosylation enzymes. Strikingly, we recently demonstrated that besides its role in regulating Golgi Mn 2þ homeostasis and consequently Golgi glycosylation, TMEM165 is sensitive to high manganese exposure. Members of the UPF0016 family contain two particularly highly conserved consensus motifs E-4-G-D-[KR]-[TS] predicted to be involved in the ion transport function of UPF0016 members. We investigate the contribution of these two specific motifs in the function of TMEM165 in Golgi glycosylation and in its Mn 2þ sensitivity. Our results show the crucial importance of these two conserved motifs and underline the contribution of some specific amino acids in both Golgi glycosylation and Mn 2þ sensitivity.

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