Generation of an Interactome for the Tetratricopeptide Repeat Domain of O‑GlcNAc Transferase Indicates a Role for the Enzyme in Intellectual Disability

The O-GlcNAc transferase (OGT) modifies
nuclear and cytoplasmic
proteins with β-N-acetyl-glucosamine (O-GlcNAc).
With thousands of O-GlcNAc-modified proteins but only one OGT encoded
in the mammalian genome, a prevailing question is how OGT selects
its substrates. Prior work has indicated that the tetratricopeptide
repeat (TPR) domain of OGT is involved in substrate selection. Furthermore,
several variants of OGT causal for X-linked intellectual disability
(XLID) occur in the TPR domain. Therefore, we adapted the BioID labeling
method to identify interactors of a TPR-BirA* fusion protein in HeLa
cells. We identified 115 interactors representing known and novel
O-GlcNAc-modified proteins and OGT interactors (raw data deposited
in MassIVE, Dataset ID MSV000085626). The interactors are enriched
in known OGT processes (e.g., chromatin remodeling) as well as processes
in which OGT has yet to be implicated (e.g., pre-mRNA processing).
Importantly, the identified TPR interactors are linked to several
disease states but most notably are enriched in pathologies featuring
intellectual disability that may underlie the mechanism by which mutations
in OGT lead to XLID. This interactome for the TPR
domain of OGT serves as a jumping-off point for future research exploring
the role of OGT, the TPR domain, and its protein interactors in multiple
cellular processes and disease mechanisms, including intellectual
disability.