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A Membraneless Organelle Associated with the Endoplasmic Reticulum Enables 3′UTR-Mediated Protein-Protein Interactions

Ma, Weirui, Mayr, Christine
Cell 2018 v.175 no.6 pp. 1492-1506.e19
RNA-binding proteins, amino acid sequences, endoplasmic reticulum, functional diversity, genes, granules, humans, membrane proteins, messenger RNA, protein-protein interactions
Approximately half of human genes generate mRNAs with alternative 3′ untranslated regions (3′UTRs). Through 3′UTR-mediated protein-protein interactions, alternative 3′UTRs enable multi-functionality of proteins with identical amino acid sequence. While studying how information on protein features is transferred from 3′UTRs to proteins, we discovered that the broadly expressed RNA-binding protein TIS11B forms a membraneless organelle, called TIS granule, that enriches membrane protein-encoding mRNAs with multiple AU-rich elements. TIS granules form a reticular meshwork intertwined with the endoplasmic reticulum (ER). The association between TIS granules and the ER creates a subcellular compartment—the TIGER domain—with a biophysically and biochemically distinct environment from the cytoplasm. This compartment promotes 3′UTR-mediated interaction of SET with membrane proteins, thus allowing increased surface expression and functional diversity of proteins, including CD47 and PD-L1. The TIGER domain is a subcellular compartment that enables formation of specific and functionally relevant protein-protein interactions that cannot be established outside.