The unfolded protein response (UPR) is a
major signaling cascade that determines
cell fate under conditions of endoplasmic
reticulum (ER) stress. The kinetics and
amplitude of UPR responses are tightly
controlled by several feedback loops and
the expression of positive and negative
regulators. In this issue of EMBO Reports,
the Wilkinson lab uncovers a novel function
of nonsense-mediated RNA decay
(NMD) in fine-tuning the UPR [1]. NMD is
an mRNA quality control mechanism
known to destabilize aberrant mRNAs that
contain premature termination codons. In
this work, NMD was shown to determine
the threshold of stress necessary to activate
the UPR, in addition to adjusting the
amplitude of downstream responses and
the termination phase. These effects were
mapped to the control of the mRNA stability
of IRE1, a major ER stress transducer.
This study highlights the dynamic crosstalk
between mRNA metabolism and the
proteostasis network demonstrating the
physiological relevance of normal mRNA
regulation by the NMD pathway