Alternative 3' UTRs act as scaffolds to regulate membrane protein localization

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Alternative cleavage and polyadenylation (ApA) affects approximately half of human genes, producing mRNA transcripts with varying 3' untranslated region (3' UTR) lengths.
• These 3' UTRs can influence protein function and localization, even when the protein sequence remains unchanged.

Purpose of the Study:

• To investigate how alternative 3' UTRs regulate the post-translational localization and function of membrane proteins.
• To elucidate the molecular mechanism by which 3' UTRs mediate protein trafficking.

Main Methods:

• Utilized human cell lines to study the effects of alternative 3' UTRs on CD47 protein expression and localization.
• Investigated the role of the RNA-binding protein HuR (ELAVL1) and SET in mediating 3' UTR-dependent protein translocation.
• Examined the functional consequences of different CD47 3' UTR isoforms.

Main Results:

• The long 3' UTR of CD47 promotes cell surface expression, while the short 3' UTR targets the protein to the endoplasmic reticulum.
• A complex involving HuR and SET, recruited by the long CD47 3' UTR, facilitates post-translational translocation to the plasma membrane via RAC1.
• Different 3' UTR isoforms of CD47 lead to distinct protein functions.
• Long 3' UTRs of other HuR-bound genes (CD44, ITGA1, TNFRSF13C) also enhance surface protein expression.

Conclusions:

• Alternative 3' UTRs serve as crucial regulators of membrane protein localization and function, independent of RNA localization.
• 3' UTRs can act as scaffolds during translation, recruiting protein complexes to direct nascent protein transport and function.
• ApA-mediated regulation of 3' UTRs represents a widespread mechanism for generating proteome functional diversity.