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. 2024 Oct 3;84(19):3790-3809.e8.
doi: 10.1016/j.molcel.2024.08.030. Epub 2024 Sep 19.

Large-scale map of RNA-binding protein interactomes across the mRNA life cycle

Lena A Street  1 , Katherine L Rothamel  2 , Kristopher W Brannan  3 , Wenhao Jin  4 , Benjamin J Bokor  1 , Kevin Dong  4 , Kevin Rhine  4 , Assael Madrigal  4 , Norah Al-Azzam  4 , Jenny Kim Kim  1 , Yanzhe Ma  1 , Darvesh Gorhe  1 , Ahmed Abdou  1 , Erica Wolin  1 , Orel Mizrahi  5 , Joshua Ahdout  4 , Mayuresh Mujumdar  4 , Ella Doron-Mandel  1 , Marko Jovanovic  6 , Gene W Yeo  7
Affiliations

Large-scale map of RNA-binding protein interactomes across the mRNA life cycle

Lena A Street et al. Mol Cell. .

Abstract

mRNAs interact with RNA-binding proteins (RBPs) throughout their processing and maturation. While efforts have assigned RBPs to RNA substrates, less exploration has leveraged protein-protein interactions (PPIs) to study proteins in mRNA life-cycle stages. We generated an RNA-aware, RBP-centric PPI map across the mRNA life cycle in human cells by immunopurification-mass spectrometry (IP-MS) of ∼100 endogenous RBPs with and without RNase, augmented by size exclusion chromatography-mass spectrometry (SEC-MS). We identify 8,742 known and 20,802 unreported interactions between 1,125 proteins and determine that 73% of the IP-MS-identified interactions are RNA regulated. Our interactome links many proteins, some with unknown functions, to specific mRNA life-cycle stages, with nearly half associated with multiple stages. We demonstrate the value of this resource by characterizing the splicing and export functions of enhancer of rudimentary homolog (ERH), and by showing that small nuclear ribonucleoprotein U5 subunit 200 (SNRNP200) interacts with stress granule proteins and binds cytoplasmic RNA differently during stress.

Keywords: ERH; IP-MS; RBP; RNA-binding proteins; RNA-dependent protein interactions; SEC-MS; SNRNP200; interactome; mRNA life-cycle; protein-protein interactions.

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Conflict of interest statement

Declaration of interests G.W.Y. is a co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Eclipse BioInnovations. G.W.Y.’s interests have been reviewed and approved by the University of California, San Diego, in accordance with its conflict-of-interest policies.

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