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Splicing-accessible coding 3'UTRs control protein stability and interaction networks.

ABSTRACT: BACKGROUND:3'-Untranslated regions (3'UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3'UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3'UTRs upon frameshift-inducing alternative splicing in more than 10% of human and mouse protein-coding genes. RESULTS:3'UTR-encoded amino acid sequences show an enrichment of PxxP motifs and lead to interactome rewiring. Furthermore, an elevated proline content increases protein disorder and reduces protein stability, thus allowing splicing-controlled regulation of protein half-life. This could also act as a surveillance mechanism for erroneous skipping of penultimate exons resulting in transcripts that escape nonsense mediated decay. The impact of frameshift-inducing alternative splicing on disease development is emphasized by a retinitis pigmentosa-causing mutation leading to translation of a 3'UTR-encoded, proline-rich, destabilized frameshift-protein with altered protein-protein interactions. CONCLUSIONS:We describe a widespread, evolutionarily conserved mechanism that enriches the mammalian proteome, controls protein expression and protein-protein interactions, and has important implications for the discovery of novel, potentially disease-relevant protein variants.

SUBMITTER: Preussner M

PROVIDER: S-EPMC7392665 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Splicing-accessible coding 3'UTRs control protein stability and interaction networks.

Preussner Marco M Gao Qingsong Q Morrison Eliot E Herdt Olga O Finkernagel Florian F Schumann Michael M Krause Eberhard E Freund Christian C Chen Wei W Heyd Florian F

Genome biology 20200729 1

<h4>Background</h4>3'-Untranslated regions (3'UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3'UTR is longer than their coding regions, pointing to additional, unknown functions. Here, we describe a protein-coding function of 3'UTRs upon frameshift-inducing alternative splicing in more than 10% of human and mouse protein-coding genes.<h4>Results</h4>3'UTR-encoded amino acid sequences sh ...[more]

PMID: 32727563

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Project description:BackgroundThe existence of negative correlations between degrees of interacting proteins is being discussed since such negative degree correlations were found for the large-scale yeast protein-protein interaction (PPI) network of Ito et al. More recent studies observed no such negative correlations for high-confidence interaction sets. In this article, we analyzed a range of experimentally derived interaction networks to understand the role and prevalence of degree correlations in PPI networks. We investigated how degree correlations influence the structure of networks and their tolerance against perturbations such as the targeted deletion of hubs.ResultsFor each PPI network, we simulated uncorrelated, positively and negatively correlated reference networks. Here, a simple model was developed which can create different types of degree correlations in a network without changing the degree distribution. Differences in static properties associated with degree correlations were compared by analyzing the network characteristics of the original PPI and reference networks. Dynamics were compared by simulating the effect of a selective deletion of hubs in all networks.ConclusionConsiderable differences between the network types were found for the number of components in the original networks. Negatively correlated networks are fragmented into significantly less components than observed for positively correlated networks. On the other hand, the selective deletion of hubs showed an increased structural tolerance to these deletions for the positively correlated networks. This results in a lower rate of interaction loss in these networks compared to the negatively correlated networks and a decreased disintegration rate. Interestingly, real PPI networks are most similar to the randomly correlated references with respect to all properties analyzed. Thus, although structural properties of networks can be modified considerably by degree correlations, biological PPI networks do not actually seem to make use of this possibility.

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Splicing-accessible coding 3'UTRs control protein stability and interaction networks.

Publications

Splicing-accessible coding 3'UTRs control protein stability and interaction networks.

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