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The unfolded protein response is shaped by the NMD pathway
Author(s) -
Karam Rachid,
Lou ChihHong,
Kroeger Heike,
Huang Lulu,
Lin Jonathan H,
Wilkinson Miles F
Publication year - 2015
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201439696
Subject(s) - unfolded protein response , microbiology and biotechnology , biology , chemistry , endoplasmic reticulum
Abstract Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), an essential adaptive intracellular pathway that relieves the stress. Although the UPR is an evolutionarily conserved and beneficial pathway, its chronic activation contributes to the pathogenesis of a wide variety of human disorders. The fidelity of UPR activation must thus be tightly regulated to prevent inappropriate signaling. The nonsense‐mediated RNA decay (NMD) pathway has long been known to function in RNA quality control, rapidly degrading aberrant mRNA s, and has been suggested to regulate subsets of normal mRNA s. Here, we report that the NMD pathway regulates the UPR. NMD increases the threshold for triggering the UPR in vitro and in vivo , thereby preventing UPR activation in response to normally innocuous levels of ER stress. NMD also promotes the timely termination of the UPR. We demonstrate that NMD directly targets the mRNA s encoding several UPR components, including the highly conserved UPR sensor, IRE1α, whose NMD ‐dependent degradation partly underpins this process. Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD 's ability to regulate normal mRNA s.