The role of 3′UTR-protein complexes in the regulation of protein multifunctionality and subcellular localization

Abstract

<jats:title>Abstract</jats:title> <jats:p>Multifunctional proteins often perform their different functions when localized in different subcellular compartments. However, the mechanisms leading to their localization are largely unknown. Recently, 3′UTRs were found to regulate the cellular localization of newly synthesized proteins through the formation of 3′UTR-protein complexes. Here, we investigate the formation of 3′UTR-protein complexes involving multifunctional proteins by exploiting large-scale protein-protein and protein-RNA interaction networks. Focusing on 238 human ‘extreme multifunctional’ (EMF) proteins, we predicted 1411 3′UTR-protein complexes involving 54% of those proteins and evaluated their role in regulating protein cellular localization and multifunctionality. We find that EMF proteins lacking localization addressing signals, yet present at both the nucleus and cell surface, often form 3′UTR-protein complexes, and that the formation of these complexes could provide EMF proteins with the diversity of interaction partners necessary to their multifunctionality. Our findings are reinforced by archetypal moonlighting proteins predicted to form 3′UTR-protein complexes. Finally, the formation of 3′UTR-protein complexes that involves up to 17% of the proteins in the human protein-protein interaction network, may be a common and yet underestimated protein trafficking mechanism, particularly suited to regulate the localization of multifunctional proteins.</jats:p>

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

“…Interestingly, some of these proteins lack a localization signal but are known to localize in the plasma membrane. The authors proposed that in the absence of any conventional localization signals, these multiple 3 0 -UTRprotein complexes might have a role in a more common but not yet disclosed protein trafficking mechanism (Ribeiro et al, 2020).…”

“…A bioinformatics search for protein complexes mediated by the 3 0 -UTR using human extreme multifunctional (EMF) proteins as a model revealed that 128 EMF proteins may form thousands of 3 0 -UTR-protein complexes (Ribeiro et al, 2020). Interestingly, some of these proteins lack a localization signal but are known to localize in the plasma membrane.…”

Association of Novel C319T Variant of PITX2 Gene 3’UTR Region With Reproductive Performance in Awassi Sheep

“… 33 A recent study indicates that the 3’UTR region of genes can influence mRNA location and protein abundance through their effects on mRNA stability and translation. 34 Ribeiro et al 35 revealed that genetic information stored in gene 3’UTR can affect protein expression through protein-protein interactions.…”

Members of the CUGBP Elav‐like family of RNA‐binding proteins are expressed in distinct populations of primary sensory neurons

“…For example, RBP binding to 3′UTRs on nascent transcripts regulates poly(A) signal site selection, cleavage, and polyadenylation (e.g., review: Tian & Manley, 2013). On mature transcripts, 3′UTRs contain interaction sites (originally termed “zip‐code” motifs [Kislauskis & Singer, 1992; Kislauskis et al., 1994; Ross et al., 1997]), for subcellular trafficking (Arora et al., 2022; Kim et al., 2015; Ribeiro et al., 2020; Yergert et al., 2021) anchoring points for scaffolding interactions (Sahoo et al., 2018) and interaction sites for recruitment of miRNAs (Grimson et al., 2007; Majoros & Ohler, 2007) or inhibition by competition for binding sites (Srikantan et al., 2012).…”