mRNA decay is critical to post-transcriptional regulation of gene expression. Removal of the 5′ 7-methylguanosine (m7G) cap is the first step of 5′-3′ mRNA decay. Three NUDIX hydrolases involved in canonical m7G-cap decapping have been identified in metazoan, among which the DCP2 protein is considered as the major decapping enzyme. DCP2 functions as part of a large macromolecular decapping complex in association with regulatory proteins that conformationally gate its activity. We previously showed that DCP2 targets nearly 2000 cellular mRNAs, a majority of which are associated with P-bodies, phase-separated liquid granules enriched for 5′-3′ mRNA decay factors. However, the mechanism of DCP2 specificity remains incompletely answered. Here, we report a human microprotein called NBDY as a regulator of DCP2 specificity. NBDY localizes to P-bodies via direct interaction with the human decapping complex components EDC4 and DCP1A. Global profiling of RNA stability changes during NBDY depletion reveals more than 1400 transcripts regulated by NBDY. Particularly, fate of DCP2 substrates in NBDY knockout cells correlates with the length of 5′ untranslated region (UTR). Non-DCP2 target transcripts are stabilized by NBDY deletion as well, possibly as a result of dysregulation of alternative mRNA decay pathways. Together, we present a comprehensive model of the regulation of mRNA decapping by NBDY.

Human microprotein that shapes specificity of mRNA decay

ACS Spring 2022

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