A Conserved Splicing Silencer Dynamically Regulates O-GlcNAc Transferase Intron Retention and O-GlcNAc Homeostasis

Publication date: 1 August 2017
Source:Cell Reports, Volume 20, Issue 5
Author(s): Sung-Kyun Park, Xiaorong Zhou, Kathryn E. Pendleton, Olga V. Hunter, Jennifer J. Kohler, Kathryn A. O'Donnell, Nicholas K. Conrad
Modification of nucleocytoplasmic proteins with O-GlcNAc regulates a wide variety of cellular processes and has been linked to human diseases. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) add and remove O-GlcNAc, but the mechanisms regulating their expression remain unclear. Here, we demonstrate that retention of the fourth intron of OGT is regulated in response to O-GlcNAc levels. We further define a conserved intronic splicing silencer (ISS) that is necessary for OGT intron retention. Deletion of the ISS in colon cancer cells leads to increases in OGT, but O-GlcNAc homeostasis is maintained by concomitant increases in OGA protein. However, the ISS-deleted cells are hypersensitive to OGA inhibition in culture and in soft agar. Moreover, growth of xenograft tumors from ISS-deleted cells is compromised in mice treated with an OGA inhibitor. Thus, ISS-mediated regulation of OGT intron retention is a key component in OGT expression and maintaining O-GlcNAc homeostasis.

Graphical abstract

Teaser

O-GlcNAc transferase (OGT) modifies cellular proteins, but the mechanisms that regulate OGT expression remain unclear. Park et al. show intron retention of the OGT transcript is responsive to cellular O-GlcNAc levels. They further define an intronic splicing silencer that is necessary to maintain O-GlcNAc homeostasis in cells and tumors.


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