Subcytoplasmic location of translation controls protein output

Horste, Ellen; Zhao, Gang; Fansler, Mervin M.; Chen, Xiuzhen; Lee, Flora; Ule, Jernej; Mayr, Christine

doi:10.1101/2022.11.04.515216

Cited by 6 publications

(6 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5a,b ), both features associated with RNAs partitioning to granules 46 , 47 . Furthermore, RNAs enriched in P-bodies 48 and TIS granules 49 using fluorescence-activated particle sorting have a similar distribution to the cytosol light profile (Supplementary Fig. 5c,d ).…”

Section: Resultsmentioning

confidence: 70%

System-wide analysis of RNA and protein subcellular localization dynamics

Villanueva,

Smith,

Pizzinga

et al. 2023

Nat Methods

View full text Add to dashboard Cite

Although the subcellular dynamics of RNA and proteins are key determinants of cell homeostasis, their characterization is still challenging. Here we present an integrative framework to simultaneously interrogate the dynamics of the transcriptome and proteome at subcellular resolution by combining two methods: localization of RNA (LoRNA) and a streamlined density-based localization of proteins by isotope tagging (dLOPIT) to map RNA and protein to organelles (nucleus, endoplasmic reticulum and mitochondria) and membraneless compartments (cytosol, nucleolus and cytosolic granules). Interrogating all RNA subcellular locations at once enables system-wide quantification of the proportional distribution of RNA. We obtain a cell-wide overview of localization dynamics for 31,839 transcripts and 5,314 proteins during the unfolded protein response, revealing that endoplasmic reticulum-localized transcripts are more efficiently recruited to cytosolic granules than cytosolic RNAs, and that the translation initiation factor eIF3d is key to sustaining cytoskeletal function. Overall, we provide the most comprehensive overview so far of RNA and protein subcellular localization dynamics.

show abstract

Section: Resultsmentioning

confidence: 70%

System-wide analysis of RNA and protein subcellular localization dynamics

Villanueva,

Smith,

Pizzinga

et al. 2023

Nat Methods

View full text Add to dashboard Cite

show abstract

“…TIS-granules serve to concentrate particular mRNAs and promote co-translational protein-protein interactions and assembly of protein complexes 21,26 . Interestingly, we find that genes that exhibit 3′UTR shortening in our dataset are significantly enriched for genes that are bound by TIS11B 27 (Fig. 1E).…”

Section: Genes That Undergo Apa Upon T Cell Activation Are Enriched F...mentioning

confidence: 80%

“…By contrast, there is no enrichment of genes with activation-regulated APA for binding to LARP4B (Fig. 1F), which marks mRNAs for localization to the diffuse cytosol 27 . This data suggests that the functional impact of 3′UTR shortening in T cells may include TIS11B-dependent regulation of protein interactions even in the absence of changes in protein or gene abundance.…”

Section: Genes That Undergo Apa Upon T Cell Activation Are Enriched F...mentioning

confidence: 96%

Alternative 3′UTR expression induced by T cell activation is regulated in a temporal and signal dependent manner

Blake,

Gazzara,

Breuer

et al. 2024

Sci Rep

View full text Add to dashboard Cite

The length of 3′ untranslated regions (3′UTR) is highly regulated during many transitions in cell state, including T cell activation, through the process of alternative polyadenylation (APA). However, the regulatory mechanisms and functional consequences of APA remain largely unexplored. Here we present a detailed analysis of the temporal and condition-specific regulation of APA following activation of primary human CD4+ T cells. We find that global APA changes are regulated temporally and CD28 costimulatory signals enhance a subset of these changes. Most APA changes upon T cell activation involve 3′UTR shortening, although a set of genes enriched for function in the mTOR pathway exhibit 3′UTR lengthening. While upregulation of the core polyadenylation machinery likely induces 3′UTR shortening following prolonged T cell stimulation; a significant program of APA changes occur prior to cellular proliferation or upregulation of the APA machinery. Motif analysis suggests that at least a subset of these early changes in APA are driven by upregulation of RBM3, an RNA-binding protein which competes with the APA machinery for binding. Together this work expands our understanding of the impact and mechanisms of APA in response to T cell activation and suggests new mechanisms by which APA may be regulated.

show abstract

“…S6A). Beyond stability, APA can also affect the rate of translation (Mayr, 2016), as well as the trafficking and localization of mRNAs (Berkovits and Mayr, 2015;Horste et al, 2023). To assess the functional enrichment of TDP-43 targets that are regulated by APA, we performed GO analysis on transcripts with a longer 3'UTR in TDP-43-depleted MNs.…”

Section: Upf1 and Tdp-43 Regulate The Polyadenylation And 3'utr Lengt...mentioning

confidence: 99%

ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3’UTR Length

Alessandrini,

Wright,

Kurosaki

et al. 2024

Preprint

View full text Add to dashboard Cite

UPF1-mediated decay entails several mRNA surveillance pathways that play a crucial role in cellular homeostasis. However, the precise role of UPF1 in postmitotic neurons remains unresolved, as does its activity in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease characterized by TDP-43 pathology and disrupted mRNA metabolism. Here, we used human iPSC-derived spinal motor neurons (MNs) to identify mRNAs subject to UPF1 degradation by integrating RNA-seq before and after UPF1 knockdown with RIP-seq to identify RNAs that co-immunoprecipitate with the active form of phosphorylated UPF1. We define a stringent set of bona fide UPF1 targets in MNs that are functionally enriched for autophagy and structurally enriched for GC-rich and long 3' UTRs but not for premature termination codon (PTC)-containing transcripts. TDP-43 depletion in iPSC-derived MNs reduces UPF1 phosphorylation and consequently post-transcriptional upregulation of UPF1 targets, suggesting that TDP-43 dysfunction compromises UPF1-mediated mRNA surveillance. Intriguingly, our datasets reveal that UPF1 and TDP-43 regulate alternative polyadenylation and 3'UTR length of mRNAs associated with synaptic and axonal function, a process that we find to be compromised in ALS models in vitro and ALS patient tissue. Our study provides a comprehensive description of UPF1-mediated mRNA decay activity in neurons, reveals overlapping roles between UPF1 and TDP-43 in regulating 3'UTR length, and offers novel insight into the intricate interplay between RNA metabolism and neurodegeneration in ALS.

show abstract

Subcytoplasmic location of translation controls protein output

Cited by 6 publications

References 89 publications

System-wide analysis of RNA and protein subcellular localization dynamics

System-wide analysis of RNA and protein subcellular localization dynamics

Alternative 3′UTR expression induced by T cell activation is regulated in a temporal and signal dependent manner

ALS-Associated TDP-43 Dysfunction Compromises UPF1-Dependent mRNA Metabolism Pathways Including Alternative Polyadenylation and 3’UTR Length

Contact Info

Product

Resources

About