The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis

• Published in: Nature communications 2020-05, Vol.11 (1), p.2619-2619, Article 2619
• Main Authors: Pirouz, Mehdi, Wang, Chih-Hao, Liu, Qi, Ebrahimi, Aref G., Shamsi, Farnaz, Tseng, Yu-Hua, Gregory, Richard I.
• Format: Article
• Language: English
• Subjects: 13; 13/100; 38/39; 38/71; 38/90; 42/89; 45; 45/91; 631/337/384; 631/337/574; 631/532/2117; 631/80/304; 631/80/642/1463; 64/60; Animals; Calcium; Calcium (intracellular); Calcium - metabolism; Calcium homeostasis; Calcium ions; Calcium Signaling - genetics; Calcium signalling; Cell Differentiation; Differentiation (biology); Embryo cells; Embryonic Stem Cells; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Exonuclease; Exoribonucleases - deficiency; Exoribonucleases - genetics; Exoribonucleases - metabolism; Fetal Macrosomia - enzymology; Fetal Macrosomia - genetics; Fetal Macrosomia - microbiology; Gene Expression Regulation; Homeostasis; Humanities and Social Sciences; Humans; Insulin - metabolism; Intracellular; Intracellular signalling; Mice; mRNA; multidisciplinary; Mutation; Non-coding RNA; Protein Biosynthesis; Quality control; Ribonuclease MRP; Ribonucleic acid; RNA; RNA, Messenger - metabolism; RNA, Small Cytoplasmic - metabolism; Science; Science (multidisciplinary); Signal recognition particle; Signal Recognition Particle - metabolism; Stem cell transplantation; Stem cells; Translation; Uridine Monophosphate - metabolism; Wilms Tumor - enzymology; Wilms Tumor - genetics; Wilms Tumor - microbiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16418-y

DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs (ncRNAs) including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and RMRP. While mutations in DIS3L2 are associated with Perlman syndrome, the biological significance of impaired DMD is obscure and pathological RNAs have not been identified. Here, by ribosome profiling (Ribo-seq) we find specific dysregulation of endoplasmic reticulum (ER)-targeted mRNA translation in DIS3L2-deficient cells. Mechanistically, DMD functions in the quality control of the 7SL ncRNA component of the signal recognition particle (SRP) required for ER-targeted translation. Upon DIS3L2 loss, sustained 3’-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage. Consequently, elevated intracellular calcium in DIS3L2-deficient cells activates calcium signaling response genes and perturbs ESC differentiation. Thus, DMD is required to safeguard ER-targeted mRNA translation, intracellular calcium homeostasis, and stem cell differentiation. The DIS3L2 exonuclease degrades aberrant 7SL RNAs tagged by an oligouridine 3′-tail. Here the authors analyze DIS3L2 knockout mouse embryonic stem cells and suggest that DIS3L2-mediated quality control of 7SL RNA is important for ER-mediated translation and calcium ion homeostasis.