Ribosome Reinitiation Directs Gene-specific Translation and Regulates the Integrated Stress Response

Young, Sara K.; Willy, Jeffrey A.; Wu, Cheng; Sachs, Matthew S.; Wek, Ronald C.

doi:10.1074/jbc.m115.693184

Cited by 76 publications

(119 citation statements)

References 25 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Despite being designated a constitutively expressed targeting subunit for type 1 protein phosphatase dephosphorylation of eIF2␣-P, Crep expression was previously reported to be sharply reduced upon overexpression of GADD34 (10), suggesting an unexplored cross-regulation between the Crep and Gadd34 genes. The changes in ribosome biogenesis and eIF2␣-P described herein emphasize the importance of regulation of NMP4 in Gadd34 and c-Myc expression in the maintenance of cellular homeostasis and provide a better understanding of the processes that maintain appropriate levels of protein synthesis in highly secretory tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Spleen, liver, and bone marrow tissues were isolated from Nmp4 ϩ/ϩ and Nmp4 Ϫ/Ϫ mice, and protein lysates were collected and quantified from the tissues and MSPCs followed by immunoblot analyses as previously described (10). Antibodies used for immunoblot analyses are listed in Table 1.…”

Section: Mice-wt and Nmp4mentioning

confidence: 99%

“…Lysates were collected, sheared, and layered on top of 10 -50% sucrose gradients as described (10). Whole-cell lysate polysome profiles were measured with a Piston Gradient Fractionator (BioComp) and a 254-nm UV monitor with Data Quest Software.…”

Section: Mice-wt and Nmp4mentioning

confidence: 99%

“…ATF4 also directly induces the transcriptional expression of Gadd34 (Ppp1r15A), which targets type 1 protein phosphatase for dephosphorylation of eIF2␣-P (7-9). Translational expression of Gadd34 is also enhanced by eIF2␣-P, and the resulting increased GADD34 serves in feedback control that restores protein synthesis, allowing for translational expression of UPR gene transcripts (7,10,11).UPR-directed transcription is also driven by IRE1, a riboendonuclease that facilitates splicing of Xbp1 mRNA, leading to translation of an activated version of the XBP1 transcription factor. In response to ER stress, ATF6 is transported from the ER to Golgi for proteolytic cleavage that allows for release of the amino-terminal portion of ATF6 to enter the nucleus and direct transcription of targeted UPR genes (1).…”

mentioning

confidence: 99%

“…ATF4 also directly induces the transcriptional expression of Gadd34 (Ppp1r15A), which targets type 1 protein phosphatase for dephosphorylation of eIF2␣-P (7)(8)(9). Translational expression of Gadd34 is also enhanced by eIF2␣-P, and the resulting increased GADD34 serves in feedback control that restores protein synthesis, allowing for translational expression of UPR gene transcripts (7,10,11).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Young¹,

Shao

Bidwell

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The unfolded protein response (UPR) maintains protein homeostasis by governing the processing capacity of the endoplasmic reticulum (ER) to manage ER client loads; however, key regulators within the UPR remain to be identified. Activation of the UPR sensor PERK (EIFAK3/PEK) results in the phosphorylation of the ␣ subunit of eIF2 (eIF2␣-P), which represses translation initiation and reduces influx of newly synthesized proteins into the overloaded ER. As part of this adaptive response, eIF2␣-P also induces a feedback mechanism through enhanced transcriptional and translational expression of Gadd34 (Ppp1r15A), which targets type 1 protein phosphatase for dephosphorylation of eIF2␣-P to restore protein synthesis. Here we describe a novel mechanism by which Gadd34 expression is regulated through the activity of the zinc finger transcription factor NMP4 (ZNF384, CIZ). NMP4 functions to suppress bone anabolism, and we suggest that this occurs due to decreased protein synthesis of factors involved in bone formation through NMP4-mediated dampening of Gadd34 and c-Myc expression. Loss of Nmp4 resulted in an increase in c-Myc and Gadd34 expression that facilitated enhanced ribosome biogenesis and global protein synthesis. Importantly, protein synthesis was sustained during pharmacological induction of the UPR through a mechanism suggested to involve GADD34-mediated dephosphorylation of eIF2␣-P. Sustained protein synthesis sensitized cells to pharmacological induction of the UPR, and the observed decrease in cell viability was restored upon inhibition of GADD34 activity. We conclude that NMP4 is a key regulator of ribosome biogenesis and the UPR, which together play a central role in determining cell viability during endoplasmic reticulum stress.Professional secretory cells balance the synthesis, folding, and trafficking of proteins to ensure optimal protein export.Upon differentiation and physiological cues, increased synthesis of polypeptides slated for secretion can lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) 3 that trigger the unfolded protein response (UPR) (1). The UPR features multiple sensory proteins, including PERK (EIF2AK3/ PEK), IRE1 (ERN1), and ATF6, which are each situated in the ER and are activated by unfolded proteins in the ER (1). Induction of the UPR leads to a program of translational and transcriptional gene expression that collectively serve to expand the processing capacity of the ER to effectively manage an expanded ER client load (1).In response to ER stress, PERK phosphorylates the ␣ subunit of eIF2 (eIF2␣-P), which represses global translation initiation that reduces influx of newly synthesized proteins into the overloaded ER (2, 3). Coincident with dampening of global protein synthesis, eIF2␣-P leads to preferential translation of Atf4, encoding a transcription activator of UPR genes involved in nutrient import, metabolism, and alleviation of oxidative stress (4 -6). ATF4 also directly induces the transcriptional expression of Gadd34 (Ppp1r15A), which targets ty...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Mice-wt and Nmp4mentioning

confidence: 99%

Section: Mice-wt and Nmp4mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Young¹,

Shao

Bidwell

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

Fernandes

Romão

2020

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Upstream open reading frames (uORFs) are cis ‐acting elements, located before or overlapped with the main coding ORF (mORF), that regulate cap‐dependent translation efficiency in a transcript‐specific manner. More than half of the human transcripts bear at least one uORF. In addition, it has been recently revealed that many of these uORFs initiate at non‐AUG codons, which significantly increases the complexity and diversity of the human translatome. These regulons are considered repressors of downstream translation but, in some biological contexts, they induce mORF expression. There are several the mechanisms by which AUG and non‐AUG uORFs regulate gene expression, allowing the cell to control transcript‐specific translation according to its needs. Also, we describe several examples of uORF genetic variants associated with human genetic diseases. Studying these cases and understanding the resultant abnormal mechanisms of uORF‐mediated translational control is of extreme importance for the development of new therapeutic strategies. Key Concepts Upstream open reading frames (uORFs) are cis ‐acting translational regulatory elements present within the 5′ leader sequence of mRNAs. uORFs can regulate gene expression by repressing or promoting translation of the downstream main ORF (mORF), according to the cellular environment. The number of uORFs, the intercistronic distance, the overlap with the mORF and the context of the initiation codon are the uORF‐related structural features that most influence their translational regulatory capacity. uORF‐mediated repression of mORF translation is usually achieved by ribosome dissociation, ribosome stalling, induction of nonsense‐mediated mRNA decay (NMD) or production of inhibitory peptides. uORF‐mediated induction of mORF translation is usually achieved by ribosome bypass or translation reinitiation. uORFs initiated by non‐AUG codons are more frequent than previously appreciated, having important biological functions. uORF‐altering polymorphisms and mutations, which create, disrupt or change a uORF, can cause human genetic diseases. Studying and understanding the uORF‐mediated mechanisms of gene expression regulation may provide knowledge to develop novel therapies for several human diseases.

show abstract

Responses of tea plants (Camellia sinensis) with different low‐nitrogen tolerances during recovery from nitrogen deficiency

Ruan

Wei

et al. 2021

J Sci Food Agric

View full text Add to dashboard Cite

BACKGROUND: Tea plants have high nitrogen (N) consumptions, whereas molecular and physiological responses of tea plants to N recovery are still unclear. RESULTS: By using non-invasive micro-test technology (NMT), 15 N tracer technique, ultra-performance liquid chromatography (UPLC), and transcriptome sequencing technology, we investigated the N recovery-induced changes in N absorptions, N tissue distributions, contents of free amino acids (FAAs), and global transcription of the low-N tolerant and intolerant tea genotypes [i. e. Wuniuzao (W) and Longjing43 (L)]. The results showed that the phenotype of Wuniuzao was better than that of Longjing43 under low-N condition. The N absorption and utilization of Wuniuzao were superior to Longjing43 under N recovery. The γ-aminobutyric acid (GABA) ratio (N recovery/N deficiency) in the root of Wuniuzao was significantly higher than that of Longj-ing43, while the glutamic acid ratio in the root of Wuniuzao was significantly lower than that of Longjing43. This findings suggested that Wuniuzao tended to enhance the GABA synthesis, while Longjing43 tended to inhibit the GABA synthesis under N recovery. The key genes in response to N recovery in Wuniuzao included N transport (AMT and NRT), N transformation (NR, NirA, and GAD), and amino acid transport (GAT) genes. In addition, some ribosome and flavonoid biosynthesis genes might help to maintain proteome homeostasis. CONCLUSION:The N absorption and transport, and the conversion abilities of key amino acids (Glu and GABA) might improve the adaptability of tea plants to N recovery, which provided a basis for the breeding of N efficient tea varieties.

show abstract

Ribosome Reinitiation Directs Gene-specific Translation and Regulates the Integrated Stress Response

Cited by 76 publications

References 25 publications

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Nuclear Matrix Protein 4 Is a Novel Regulator of Ribosome Biogenesis and Controls the Unfolded Protein Response via Repression of Gadd34 Expression

Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

Responses of tea plants (Camellia sinensis) with different low‐nitrogen tolerances during recovery from nitrogen deficiency

Contact Info

Product

Resources

About