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ZAP triggers mRNA decay during the regulation of aberrant protein production

ABSTRACT: The endoplasmic reticulum (ER) is essential for the proper folding and processing of secretory and membrane proteins. These proteins are guided to the ER by signal peptides recognized by the signal recognition particle (SRP). When this process is impaired, cells rely on quality control mechanisms to prevent the accumulation of misfolded or mislocalized proteins. One such mechanism, known as regulation of aberrant protein production (RAPP), targets mRNAs encoding mutated signal peptides for degradation and also eliminates the corresponding aberrant proteins. Using a functional genetic screen, we identify the zinc finger antiviral protein (ZAP) as a key component of the RAPP pathway. Using proteomics and enhanced UV crosslinking and immunoprecipitation (eCLIP) experiments, we show that ZAP-S isoform associates with SRP components and facilitates degradation of aberrant mRNAs and proteins. ZAP exerts its role by recognizing faulty proteins early in their biogenesis and targeting them, along with their encoding mRNAs, for degradation. Loss of ZAP activates ER stress and the integrated stress response, highlighting its central role in safeguarding protein targeting and maintaining cellular homeostasis.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Colin Wu

PROVIDER: MSV000099053 | MassIVE |

REPOSITORIES: MassIVE

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Project description:Spatial organization of the transcriptome has emerged as a powerful means for regulating the post-transcriptional fate of RNA in eukaryotes; however, whether prokaryotes use RNA spatial organization as a mechanism for post-transcriptional regulation remains unclear. Here we used super-resolution microscopy to image the E. coli transcriptome and observed a genome-wide spatial organization of RNA: mRNAs encoding inner-membrane proteins are enriched at the membrane, whereas mRNAs encoding outer-membrane, cytoplasmic and periplasmic proteins are distributed throughout the cytoplasm. Membrane enrichment is caused by co-translational insertion of signal peptides recognized by the signal-recognition particle. Our time-resolved RNA-sequencing and live-cell super-resolution imaging experiments revealed a physiological consequence of this spatial organization and the underlying mechanism: membrane localization enhances degradation rates of inner-membrane-protein mRNAs by placing them in proximity to membrane-bound RNA degradation enzymes. Together, these results demonstrate that the bacterial transcriptome is spatially organized and that this organization shapes the posttranscriptional Spatial organization of the transcriptome has emerged as a powerful means for regulating the post-transcriptional fate of RNA in eukaryotes; however, whether prokaryotes use RNA spatial organization as a mechanism for post-transcriptional regulation remains unclear. Here we used super-resolution microscopy to image the E. coli transcriptome and observed a genome-wide spatial organization of RNA: mRNAs encoding inner-membrane proteins are enriched at the membrane, whereas mRNAs encoding outer-membrane, cytoplasmic and periplasmic proteins are distributed throughout the cytoplasm. Membrane enrichment is caused by co-translational insertion of signal peptides recognized by the signal-recognition particle. Our time-resolved RNA-sequencing and live-cell super-resolution imaging experiments revealed a physiological consequence of this spatial organization and the underlying mechanism: membrane localization enhances degradation rates of inner-membrane-protein mRNAs by placing them in proximity to membrane-bound RNA degradation enzymes. Together, these results demonstrate that the bacterial transcriptome is spatially organized and that this organization shapes the post-transcriptional dynamics of mRNAs.

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ZAP triggers mRNA decay during the regulation of aberrant protein production

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