Stress and the nonsense-mediated RNA decay pathway

Abstract

Cells respond to internal and external cellular stressors by activating stress-response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway-nonsense-mediated RNA decay (NMD)-serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting that it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that "NMD therapy" may provide clinical benefit by downmodulating stress responses.

Keywords: Apoptosis; Autophagy; Stress granules; eIF2α phosphorylation.

Fig. 1

NMD degrades a subset of both aberrant and normal RNAs. Its ability to degrade aberrant RNAs with premature termination codons serves as a quality control mechanism. Its ability to degrade normal transcripts allows NMD to influence a variety of events, including those shown

Fig. 2

NMD degrades mRNAs encoding UPR components. A simplified diagram depicting the three UPR pathways, activated by the PERK, IRE1, and ATF6 sensors, respectively. When chaperones, including BiP and TNRC5, leave these sensors to bind unfolded proteins, the sensors activate intracellular signaling, leading to transcriptional activation, as shown. UPR components encoded by high-confidence NMD target RNAs are designated in red font; UPR components encoded by mRNAs that less evidence suggests are NMD target mRNAs are designated in black font. XBP1u XBP1 unspliced, XBP1s XBP1 spliced isoform

Fig. 3

NMD promotes timely termination of the UPR. a The UPR can be thought of as a clock. If the stress is resolved in a timely manner, the result is homeostasis. Alternatively, prolonged stress leads to apoptosis. NMD promotes both maintenance of homeostasis and timely termination of the UPR. b NMD is suppressed by the UPR to allow for maximal activation of the UPR pathway. After the resolution of the stress, the UPR is downregulated, which is thought to rescue normal levels of NMD, thereby leading to further downregulation of the UPR. This regulatory spiral eventually leads to complete shut-off of the UPR pathway. c In chronic stress, the UPR is constitutively activated and NMD is suppressed, which, together, typically leads to apoptosis

Fig. 4

UPR inhibits NMD through eIF2α phosphorylation, a post-translational event that gives rise to stress granules (SGs). Various stressors—including ER stress, hypoxia, chemical agents, and viruses—can trigger eIF2α phosphorylation. This phosphorylation event causes the formation of stress granules, which are enriched in translationally arrested mRNAs. NMD requires translation and thus SGs may be subcellular sites where NMD is repressed. NMD promotes SG formation, suggesting the existence of a negative feedback loop. SGs are also considered to be sites where small RNAs such as miRNAs are functionally silenced

Fig. 5

Model for how NMD regulates autophagy and amino-acid availability. The PERK arm of the UPR, as well as other cues, including Rapamycin, can trigger autophagy in cells via induction of ATF4, a transcription factor that, in turn, drives the expression of another transcription factor, CHOP. CHOP activates transcription of genes encoding essential autophagy factors, including those shown in the figure. ATF4 and CHOP are both encoded by NMD target mRNAs, providing a molecular basis for how high NMD activity represses autophagy. Since amino acids are recycled by autophagy, one downstream consequence of this regulation is altered amino-acid availability. NMD also impacts amino-acid availability by repressing the expression of the cystine-glutamate transporter xCT. NMD targets SLC7A11 mRNA, which encodes one of the subunits of this amino-acid transporter

Fig. 6

NMD and apoptosis have a complex regulatory relationship I. NMD provides protection from apoptosis-inducing agents, including chemotherapeutic drugs. Evidence suggests that NMD achieves this through its targeting of Gas5 and Gadd45 RNAs, both of which promote apoptosis signaling. Not only does NMD regulate apoptosis, but apoptosis-inducing agents can impact NMD. In the example depicted, chemotherapeutic agents trigger cleavage of the NMD factor, UPF1, which downregulates NMD

Fig. 7

NMD and apoptosis have a complex regulatory relationship II. a NMD inhibits cell death triggered by apoptosis-inducing agent. b Sustained and/or strong stress leads to suppression of NMD, thereby triggering apoptosis