TMEM165, a Golgi-localized protein belonging to the uncharacterized protein family 0016 (UPF0016), is likely a transporter involved in ion homeostasis. It is crucial for Golgi functions, playing a role in pathways related to protein and lipid glycosylation. Its deficiency leads to Congenital Disorders of Glycosylation (CDG), highlighting its biological importance. Studies using TMEM165-deficient mammalian cells or yeast cells deficient in Gtd1p (the yeast ortholog) have been valuable in deducing its function in the secretory pathway [1].

In TMEM165-depleted cells, there are Golgi glycosylation defects due to impaired Golgi Mn²⁺ homeostasis. Mn²⁺ supplementation can rescue the Mn content in the secretory pathway/organelles and the glycosylation process, suggesting TMEM165 is involved in cellular Mn²⁺ homeostasis [2]. In conditional, tissue-specific knockout mice, TMEM165 was found crucial in the lactating mammary gland for normal lactose biosynthesis and normal growth rates of nursing pups. It supplies Ca²⁺ and Mn²⁺ to the Golgi complex in exchange for H⁺ to sustain the functions of lactose synthase and potentially other glycosyl-transferases [3].

In conclusion, TMEM165 functions as a Ca²⁺/Mn²⁺:H⁺ antiporter in the Golgi, regulating ion homeostasis which is essential for glycosylation processes. Deficiency in TMEM165 leads to CDG, and its study in knockout models, like the tissue-specific knockout mice, has provided insights into its role in biological processes such as milk biosynthesis and glycosylation-related diseases.