10 years ago, we and others found that at least half of human genes generate mRNA isoforms with alternative 3′UTRs, meaning that a specific protein can be encoded by an mRNA containing a short or a long 3′UTR isoform (Mayr, 2009)(Lianoglou, 2013). Traditionally, it has been thought that 3′UTRs regulate mRNA-based processes, including mRNA stability, translation, and mRNA localization (Mayr, 2018a). Although 3′UTRs often regulate protein abundance of short-lived mRNAs, including oncogenes (Mayr 2009), genome-wide studies by us and others found that generally less than 20% of significant 3′UTR isoform changes are associated with changes in their corresponding mRNA or protein expression levels (Lianoglou, 2013). Therefore, it is largely unknown how alternative 3′UTRs contribute to biology (Mayr, 2016)(Mayr, 2017).
Regulation of protein functions by 3′UTRsAlthough 3′UTRs are not part of proteins, we have obtained evidence in the last few years that 3′UTRs regulate protein functions. We discovered this function while studying the alternative 3′UTR isoforms of CD47. We found that CD47 protein that was encoded by the CD47 mRNA isoform with the long 3′UTR (CD47-LU) interacts with SET, whereas CD47 protein encoded from the short 3′UTR isoform (CD47-SU) does not. This means that the protein-protein interaction between SET and CD47-LU is mediated by its long 3′UTR. SET binding has important functional consequences for CD47: it promotes CD47 plasma membrane localization, thus, protecting cells better from phagocytosis by macrophages, but it also recruits RAC1, allowing active signaling and cell migration upon expression of CD47-LU, but not of CD47-SU (Berkovits, 2015).
3′UTR-mediated protein-protein interactions are not restricted to CD47 as also the alternative 3′UTRs of BIRC3 determine different protein functions (Lee, 2018). Our current data suggest that 3′UTR-mediated recruitment of proteins can serve different purposes: (i) it can diversify protein functions, as is the case for the E3 ubiquitin ligase BIRC3. BIRC3-SU performs the canonical protein functions, whereas BIRC3-LU can accomplish new functions that are specific to BIRC3-LU. This type of functional diversification of proteins does not require a change in amino acid sequence and we propose that this function of 3′UTRs may contribute to the regulation of increased biological complexity during evolution. The substantial expansion of 3′UTR sequences during the evolution of higher organisms may allow the emergence of multi-functionality of proteins (Mayr, 2017).Our data on CD47 suggest that 3′UTR-mediated recruitment of proteins may assist in the last step of functional biogenesis (ii). It seems that after translation and folding, CD47 protein may not yet be functionally fully competent. Binding of the biogenesis factor SET to CD47 enables proper protein localization and may render CD47 functionally fully competent as it allows activation of specific signaling pathways.
We further hypothesize that co-translational recruitment of proteins mediated by 3′UTRs can assist in the first step of protein biogenesis (iii). Through recruitment of chaperones 3′UTRs may assist the folding of proteins and may prevent formation of potentially toxic aggregates (Mayr, 2018b).
In summary, our data indicate that 3′UTRs contain genetic information that can be transmitted to proteins via 3′UTR-mediated protein-protein interactions and can influence diverse protein features.