O-GlcNAc regulated arginine methylation: a novel paradigm in survival signaling

The dynamic modification of intracellular proteins by monosaccharides
of O-linked β-N-acetylglucosamine (O-GlcNAc) has
emerged as a novel regulator of cytoprotection. In response to
cellular stress and injury, O-GlcNAc levels are elevated on numerous
proteins in a dose-dependent manner. Suggesting that this
is an endogenous survival signal, elevating O-GlcNAc levels
before or after the induction of injury is protective in both in
vivo and in vitro models. In order to investigate the molecular
mechanisms that underlie this protective phenotype, we have
identified proteins whose O-GlcNAcylation status changes with
cellular injury. In this study, we report that protein arginine
methyltransferase 1 (PRMT1) is O-GlcNAc modified and associates
with the O-GlcNAc transferase (OGT; catalyzes the addition
of O-GlcNAc). Suggesting that OGT/ O-GlcNAc regulates the
activity of PRMT1, deletion or inhibition of OGT leads to an increase
in the arginine modification catalyzed by PRMT1: assymetric
dimethylation. In vitro assays demonstrate that the
physical association of OGT with PRMT1 leads to an inhibition
of PRMT1 activity. To assess the role of O-GlcNAc regulated arginine
methylation in cellular injury, PRMT1 activity was inhibited
pharmacologically or genetically in cells with lower levels of
O-GlcNAc. Cells with reduced O-GlcNAcylation are more sensitive
to oxidative stress when compared to untreated cells, and
this sensitivity can be ablated by PRMT1 knockdown or inhibition.
PRMT1 is thought to promote cell death by methylating
proteins such as Bad and Foxo, preventing their phosphorylation
by Akt. Consistent with a hypothesis in which O-GlcNAc promotes
Akt phosphorylation and survival, the pro-apoptotic
protein Bad is hypophosphorylated in the OGT null and this can
be reversed by inhibition or knockdown of PRMT1. Together,
these demonstrate that OGT may be as important as it’s catalytic
activity in promoting cell survival during injury and highlight
one mechanism by which OGT/ O-GlcNAc protects cells and
tissues.