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Multiomics Analysis of TMEM200A as a Pan-Cancer Biomarker
Published on: September 15, 2023
Impact of disease-causing mutations on TMEM165 subcellular localization, a recently identified protein involved in
Claire Rosnoblet1, Dominique Legrand, Didier Demaegd
1CNRS-UMR 8576, Structural and Functional Glycobiology Unit, IFR 147, University of Lille 1, 59655 Villeneuve d’Ascq, France.
Abstract:
TMEM165 has recently been identified as a novel protein involved in CDG-II. TMEM165 has no biological function described so far. Different mutations were recently found in patients with Golgi glycosylation defects and harboring a peculiar skeletal phenotype. In this study, we examined the effect of naturally occurring mutations on the intracellular localization of TMEM165 and their abilities to complement the TMEM165-deficient yeast, gdt1▵. Wild-type TMEM165 was present within Golgi compartment, plasma membrane and late endosomes/lysosomes, whereas mutated TMEM165 were found differentially localized according to the mutations. We demonstrated that, in the yeast functional assay with TMEM165 ortholog Gdt1, the homozygous point mutation correlating with a mild phenotype restores the yeast functional assay, whereas the truncated mutation, associated with severe disease, failed to restore Gdt1 function. These studies highly suggest that these clinically relevant point mutations do not affect the protein function but critically changes the subcellular protein localization. Moreover, the data point to a critical role of the YNRL motif in TMEM165 subcellular localization.
Insights
Transmembrane protein 165 (TMEM165) mutations impact Golgi glycosylation defects. Specific mutations alter TMEM165
Area of Science:
- Cell Biology
- Genetics
- Biochemistry
Background:
- Transmembrane protein 165 (TMEM165) is a novel protein implicated in Congenital Disorders of Glycosylation type II (CDG-II).
- Mutations in TMEM165 have been identified in patients exhibiting Golgi glycosylation defects and skeletal abnormalities.
- The precise biological function and subcellular localization of TMEM165 remain largely uncharacterized.
Purpose of the Study:
- To investigate the impact of naturally occurring TMEM165 mutations on its intracellular localization.
- To assess the functional consequences of these mutations using a yeast complementation assay.
- To elucidate the role of specific motifs, such as YNRL, in TMEM165 localization and function.
Main Methods:
- Utilized immunofluorescence microscopy to determine the subcellular localization of wild-type and mutant TMEM165.
- Employed a yeast functional assay involving the TMEM165 ortholog Gdt1 to assess complementation by human TMEM165 variants.
- Analyzed homozygous point mutations and truncated mutations associated with varying disease severity.
Main Results:
- Wild-type TMEM165 localizes to the Golgi, plasma membrane, and late endosomes/lysosomes.
- Mutated TMEM165 proteins exhibit differential subcellular localization patterns depending on the specific mutation.
- A homozygous point mutation linked to a mild phenotype restored yeast function, while a severe disease-associated truncation failed to complement.
- The YNRL motif was identified as critical for TMEM165 subcellular localization.
Conclusions:
- Clinically relevant point mutations in TMEM165 primarily affect its subcellular localization rather than protein function.
- Subcellular mislocalization of TMEM165 is strongly associated with Golgi glycosylation defects and skeletal phenotypes in CDG-II.
- The YNRL motif plays a crucial role in directing TMEM165 to its correct cellular compartments, influencing its biological activity.
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